iHEMICAL INVEBTieATION 2YOLIC SYSTENB WITH Si …RESUME ,.._..._ u C_ ) ! THESES SUBMITTED FOR THE...

iHEMICAL INVEBTieATION 2YOLIC SYSTENB WITH S i

iEFERENOE TO STERO

RESUME ,.._..._

u C_ ) !

T H E S E S SUBMITTED FOR THE AWARD OF THE DEGREE

ottor of m

CHEMISTRY

BY

DEPARTMENT OF CHESWIBSTRY ALIGABH MUSUIWJ UNIVERSITY

ALI6ARM (INDIAI

Previous work from our laboratories described the

preparation and study of a number of the then unknown

steroidal derivatives mainly in the cholestane and stig-

mastane series. These included azasteroids, oxasteroids,

nitrosteroids, pyrans, pyrazoles etc. In continuation of

the above work an attempt has been made to prepare new

compounds with probable biological potential. The newly

prepared compounds have been characterized on the basis

of their analytical data, spectral properties and chemical

conversions. In some cases abnormal products have been

obtained and this has offered scope for some mechanistic

and stereochemical studies also, "^he whole work is

divided into four parts namely, (1) Imidazopyridines,

(2) Benzothiazepines, (3A) Steroidal arylidines (3B) Solid

Surface Reactions, (4) Mass Spectral Studies of Benzothia

zepines.

: 11 :

PART-1

IMIDAZOPYRIDINES :

Most of the imidazopyridines show remarkable and unusual

anabolic and physiological activities. The most commonly

used method for the preparation of imidazopyridine is the

reaction of 2-aminopyridine with a-bromoketones.

It is worth mentioning that little attention has been

paid towards the synthesis of steroidal imidazopyridines.

This prompted us to undertake the present study which includes

/the preparation of some of the steroidal imidazopyridines from

appropriate a-bromo ketones belonging to cholestane and

stigmastane series. For the present study we selected some of

the easily accessible a-bromoketones and a,p-unsaturated

ketones;such as 5-bromo-6-oxo-5a-cholestane (I),6-oxocholest-

4-ene (II), 5-bromo-6-oxo-5a-cholestan-3p-yl acetate (III),

7a-bromo-6-oxo-5a-cholestan-3p-yl acetate (IV), 3,6-dioxo-

cholest-4-ene (V), 5-bromo-6-oxo-5a-cholestan-3p-yl propionate

(VI), 5-bromo-6-oxo-5a-stigmastan-3^-yl acetate (VIIj& 5-bromo-

6-oxo-5a-stigmastan-3p-yl propionate (VIII). The results are

summarized below:

: 111 :

" S l?

( I )

CsHlY

( IX )

• ( IX )

CQH

AcO

8"17 CgH T

Brb

(III)

CaHl7

(XI) (IV)

. X V •

CsHl? CsHi?

^8^17

(IV)

(XIV) 5a

(XV) 5P

-> (XIV) + (XV)

(XIII)

CQH 8"17

-> (X)

CgH-,_y CoH

->

8"17

(XVI)

: V :

1 0 ^ 2 1

AcO

P r o

F3H17

(XVII) 5a

( X V I I I ) 5^

- >

^1C^21

+

H21C10 (XIX) ^10^2

(XX) 5a

(XXI) 5^

(XXII) 5a

( X X I I I ) sp

V I • V a . •

C10^21

( V I I I )

CipuH. i c r 2 i

•i-

(XXIV)

^10^21 H r 2irio

(XXV) 5a

(XXVI) 5P

(XXVII) 5a

(XXVIII) 5P

V l l %

FART-2

BENZOTHIAZEPINES :

/^enzothiazepines are claimed to exhibit a wide spectrum

of pharmacological activities as tranquilizing, antibacterial,

neurolectic, anticonvulsive, antidepressanr etc. . The survey

of literature revealed that no attempt has been made to pre

pare steroidal benzothiazepines in stigmasxane series. Hence

with a view of synthesizing benzothiazepines in the steroidal

systems we carried out the reaction of some of the easily

accessible a,^-unsaturated ketones in the stigmastane series

such as 6-oxostigmast-4-en-3p-yl acetate (XXIX), 6-oxostigmast-

4-en-3p-yl propionate (XXX), 7-oxostigmast-5-ene (XXXI),

7-oxostigmasta-3,5-diene (XXXIl), 7-oxostigmast-5-en-3p-yl

chloride (XXXIII), 7-oxostigmast-5-en-3p-yl acetate (XXXIV),

7-oxostigmast-5-en-3p-yl propionate (XXXV)^ 3,6-dioxostigmast-

4-ene (XXXVI) with 2-amino thiophenol in absolute methanol.

(XXIX) (XXX)

^10^21

R

OAc OPr

->

R

(XXX\'II) OAc

(XXX\'III) CPr

910^21

V l l l

C10^21

R

(XXXI)

(XXXIV;

(XXXV)

H

OAc

OPr

9 1 0 ^ 2 1

(XXXII)

->

C20^2I

(XXXIX)

(XL)

(XLI)

R

H

OAc

OFr

^10^21

-> •4-

- V ( X L I I )

S N_H N , SH

/ / \ \

(XLIII)

I X

C10^21

(XXXIII)

Ci rH 1C''-21

// ^ (xLr/3

910^-21

(XLVI)

910^21 910^21

(XXXVI) (XLVII)

PART-3

[A] STEROIDAL ARYLIDEhES s

Chritiansen et al. first reported the preparation

of 16-arylicline derivatives of androstanes and androstenes

which exhibit anabolic, androgenic, pituitary inhibiting,

coronary dilatory and antihypertensive activities. The

survey of literature revealed that no arylidene derivative

of the cholestane series is reported. For the synthesis of

such derivatives we selected some ketones in cholestane

series as 3-oxocholest-4-ene (XLVIIl)^ 5,6p-dibromo-3-oxo--5a-

cholestane (XLIX), 3-oxocholesta-4,6-diene (L) and 3,6-dioxo-

cholest-4-ene (v). They were allowed to react with 4-N,N-

dimethylaminobenzaldehyde and the products obtained were

characterized on the b^sis of analytical and spectral data.

CgHj_7 98^17

(XLVIII) ( LI )

• V 1 • X I

^8^17 CgHj_7

(XLIX)

CsHl?

( L I I )

( L I I )

( L )

CgHj^y

98^17

( V ) (LIII)

: x.i :

[B] SOLID SURFACE REACTION :

Epoxy ring opening reaction on solid phase has been

reported recently. In continuation and with the interest to

study/the effect of silica gel as a solid phase, some easily

accessible steroidal epoxides! such as 3p-hydroxy-5,6a-epoxy-

5a-cholestane (LIV) and 3p-hydroxy-5,6a-epoxy-5a-stigmastane

(LV^ Were allowed to react with NaCl on silica gel at about

100 CJ The results of the preliminary study are encouraging

with some unusual products as shown in the chart. R

->

R R

(LIV)

(LV)

^8^17

• 10 21

(LVI)

(Lix;

CgHj_y

^10^21

R R

(LVII) CgH^7 (LVIII) CgH^^

(LX) ^10^21 (LXI) ^10^21

: x i i i :

PART-4

MASS SPECTRAL STUDIES Or BENZOTHIAZEPI^ES :

A survey of l i t e r a t u r e r e v e a l e d t h a t no s y s t e m a t i c mass

s p e c t r a l s t u d i e s of s t e r o i d a l b e n z o t h i a z e p i n e s has been

r e p o r t e d . I n t h e p r e v i o u s p a r t we have d e s c r i b e d t h e p repa

r a t i o n of a number of b e n z o t h i a z e p i n e s . These two events

prompted us t o examine t h e mass s p e c t r a of s e v e r a l s t r u c t u r a l l y

r e l a t e d s t e r o i d a l b e n z o t h i a z e p i n e s . These i n c l u d e 5a -cho les t an

[ 4 a , 6 - b c ] - 2 ' , 3 ' - d i h y d r o - l ' , 5 ' - b e n z o t h i a z e p i n e (LXII ) ,

5 a - c h o l e s t a n [ 4 a , 6 - - b c ] - 2 S 3 ' - d i h y d r o - l % 5 ' - b e n z o t h i a z e p i n - 3 p - y l

a c e t a t e ( L X I I I ) , 5 a - c h o l e s t a n [ 4 a , 6 - b c ] - 2 ' , 3 ' - d i h y d r o - l ' , 5 ' -

b e n z o t h i a z e p i n - 3 p - y l p r o p i o n a t e (LXIV), 5 a - s t i g m a s t a n [ 4 a j 6 - b c ] -

2 ' , 3 ' - d i h y d r o - l « , 5 « - b e n z o t h i a z e p i n - - 3 ^ - y l a c e t a t e (XXXVII),

5 a - s t i g m a s t a n [ 4 a , 6 - - b c ] ~ 2 ' , 3 * " d i h y d r o - l ' p 5 ' - b e n z o t h i a z e p i n - 3 p - y l

p r o p i o n a t e (XXXVIIi; , 5 a r - c h o l e s t a n [ 5 , 7 - b c ] - 2 ' , 3 « - d i h y d r o - l « , 5 « -

b e n z o t h i a z e p i n e (LXV), 5 a ~ c h o l e s t a n [ 5 , 7 ~ b c ] - 2 ' , 3 ' - d i h y d r o - l ' ,

5 ' - b e n z o t h i a z e p i n - 3 p - y l a c e t a t e (LXVI), 5 a - c h o l e s t a n [ 5 , 7 - b c ] -

2 ' , 3 ' - d i h y d r o - l ' , 5 « - b e n z o t h i a z e p i n - 3 p - y l c h l o r i d e (DCVII),

5 a - s t i g m a s t a n [ 5 , 7 - b c ] - 2 ' , 3 ' - d i h y d r o - l ' , 5 ' - b e n z o t h i a z e p i n e

(XXXIX), 5 a - s t i g m a s t a n - [ 5 , 7 - b c ] - 2 ' , 3 * - d i h y d r o - l « , 5 « - b e n z o t h i a -

z e p i n - 3 ^ - y l a c e t a t e (XL), 5 a - s t i g m a s t - 3 - e n - [ 5 , 7 - b c ] - 2 ' , 3 ' -

d i h y d r o - l ' , 5 ' - b e n z o t h i a z e p i n e (XLIV), N , S - p h e n y l e n e ~ 3 a - t h i o -

3 p - a m i n o c h o l e s t - 4 - e n e (LXVIII) and 6-oxo-5cc-choles tan[2a ,

4 a - b c ] - 2 * , 3 ' , 4 ' , 5 ' - t e t r a h y d r o - 1 ' , 5 ' - b e n z o t h i a z e p i n e (LXIX).

: XIV :

I t was anticipated that they wil l follow similar fragmentation

pat tern thus offering a simple and effective method for their

characterizat ion by mass spectrometry.

(LXII)

(Lx i i i ;

(DCIV)

(XXXVII)

(XXXVIII)

X

H

AcO

Pro

AcO

Pro

R

CgHj y

^8^17

^8^17

^10^21

^10^21

S \

{ (LXV)

(LXVI)

(LXVII)

(XXXIX)

(XL)

N /

3 X

H

AcO

CI

H

AcO

R

S^'l7

^8^17

^8^17

10* 21 r '-f IC- 21

910^21 CsHl? Hl7?8

(DCVIII) (LJ<IX)

CHEMICAL INVESTIGATIONS IN ALICYCLIC S Y S T E M S WITH SPECIAL

REFERENCE TO STEROIDS

T H E S I S SUBMITTED FOR THE AWARD OF THE DEGREE OF

jBottor of Pdilojioplip IN

CHEMISTRY

BY

GEETESH MUDGAb

DEPARTMENT OF CHEMISTRY ALIQARH MUSLIM UNIVERSITY

ALIGARH (INDIA)

1991

WC-v

X i . ^ ^,

Ql>-xy^^"^

I 0 SEP '392

Uam.

T4108

^002

tBECKED I996.ff ^

9, .//. .//„,//y Reader in Chemistry

Tel.: 25515

DEPARTMENT OF CHEMISTRY ALIGARH MUSLIM UNIVEKSITY

ALIGARH

ZJ«/.J..-.2t.l?.?2

This is to certify that the work embodied in

this thesis entitled 'Chemical Investigations

in Alicyclic Systems with Special Reference to

Steroids' is the originnal work done by Miss

Geetesh Mudgal under my supervision. The thesis

is suitable for submission for the award of

degree of Doctor of Philosophy in Chemistry.

r ( Dr. M. Mushflq )

Res. U-2, M.I a !• 1(11.1, DiggI Rouil, Aligarlt-202001 (U. I'.), INDIA Tel. 29226

Co Mv ^arento

^cknotolebgement

It gives me a great pleasure to express my deep sense

of gratitude to Dr. M. Mushfiq who directed these researches,

for his unstinted help, incessant encouragement and inspiring

guidance throughout the work,

I am indeoted to Prof. M.S. Ahmad who gave me valuable

suggestions in my research problems.

I am highly thankful to Prof. S.M. Osman and Prof. S.A.A.

Zaidi, Ex-chairmen and Prof. M.A. Beg, Chairman, Department of

Chemistry, AMU, for providing necessary research facilities.

Words will be inadequate in expressing my sincere thank

fulness to my friends and colleagues for their rewarding

suggestions and valuable discussions.

I am extremely thankful to Mr. Mohd. Ayub Khan and

Star Xerox for their good techniques of typing and Xerox.

I am extremely greatful to R.S.I.C., CDRI, Lucknow and

I.I.T. Madras for providing i.r., n.m.r. and mass spectra.

I wish to record my sincere thanks to U.G.C. for providing

me financial help.

Finally, but not certainly the least. It is with

immense pleasure that I record my indebtedness and heartful

gratitude to my parents, brother and sister who were always

there with me at odd times,

[GEETESH MUDGAL]

Summary

CHAPTER-CNt : I m i d a z o p y r i d i n e s

Conttntsi PAGE KC.

i - x i v

T h e o r e t i c a l • • • 1 - 1 8

D i s c u s s i o n • • • 1 9 - 4 2

E x p e r i m e n t a l • • • 4 3 - 6 6

R e f e r e n c e s • • • 6 7 - 7 2

CHAPTER-TWO : B e n z o t h i a z e p i n e s

T h e o r e t i c a l • • • 7 3 - 9 1

D i s c u s s i o n . • • 92 - 110

E x p e r i m e n t a l • • • H ^ ~ ^25

R e f e r e n c e s • • • 126 - 131

CHAPTER-THREE[A] : S t e r o i d a l A r y l i d e n e s

T h e o r e t i c a l . . . 132 - 144

D i s c u s s i o n . . . 145 - 152

E x p e r i m e n t a l . . . 153 - 159

R e f e r e n c e s . . . 160 - 162

CHAPTER-THF.EELB] : S o l i d S u r f a c e R e a c t i o n s

T h e o r e t i c a l . . . 163 - 182

D i s c u s s i o n . . . 183 - 194

E x p e r i m e n t a l . . . 195 - 199

R e f e r e n c e s . . . 2OO - 203

CHAPTER-FOUR : Mass Spectral Studies of

Steroidal Benzothiazepines

Discussion ... 204 - 261

Experimental ... 262 - 269

References ... 270 - 271

Mmmsivp

Previous work from our laboratories described the

preparation and study of a number of the then unknown

steroidal derivatives mainly in the cholestane and stig-

mastane series. These included azasteroids, oxasteroics,

nitrosteroids, pyrans, pyrazoles etc. In continuation of

the above work an attempt has been made to prepare new

compounds with probable biological potential. The newly

prepared compounds have been characterized on the basis

of their analytical data, spectral properties and chemical

conversions. In some cases abnormal products have been

obtained and this has offered scope for some mechanistic

ana stereochemical studies also. The whole work is

divided into four parts namely, (1) Imidazopyridines,

(2) Benzothiazepines, (3A) Steroidal arylidines (3B) Solid

Surface Reactions, (4) Mass Spectral Studies of Benzothia

zepines.

11

PART-1

IMIDAZOPYRIDINES :

Most of the imidazopyxidines show remarkable and unusual

anabolic and physiological activities. The most commonly

used method for the preparation of imidazopyridine is the

reaction of 2-aminopyridine with a-bromoketones.

It is worth mentioning that little attention has been

paid towards the synthesis of steroidal imidazopyridines.

This prompted us to undertake the present study which includes

the preparation of some of the steroidal imidazopyridines from

appropriate a-bromo ketones belonging to cholestane and

stigmastane series. For the present study we selected some of

the easily accessible a-bromoketones and a,p-unsaturated

ketones such as 5-bromo-6-oxo-5a-cholestane (I),6-oxocholest-

4-ene (II), b-bromo-6-oxo-5a-cholestan-3p-yl acetate (III),

7a-bromo-6-oxo-5a-cholestan-3p-yl acetate (IV), 3,6-dioxo-

cholest-4-ene (V), b-bromo-6-oxo-ba-cholestan-3p-yl propionate

(VI), 5-bromo-6-oxo-5a-stigmastan-3p-yl acetate (VII)& 5-bromo-

6-oxo-5a-stigmastan-3p-yl propionate (VIII). The results are

summarized below:

: 111 :

( I )

CsHl?

-»

C8H17

N. /N

( IX )

^ ( IX )

AcO

CoH 8"17

Bro

(III)

CsHl?

CsHlY

(XI) (IV)

CsHl-

^8^17

CsHiy

(XIV) 5a

(XV) 5p

- > (XIV) + (XV)

• ^ ( X )

C3H1

( X I I I )

"^S^l?

- >

^8^17

(XVI)

: V :

10^21

AcO

PrO

(XVII) 5a

(XVIII) 5p

-5>

^ 10 21

H21C10 (XIX) ' 10 2.

(XX) 5a

(XXI) 5p

(XXII) 5a

(XXIII) 5p

V I

^10^21

( V I I I )

^10^21

(XXIV)

C10^21 "21?10

(XXV) 5a

(XXVI) 5p

(XXVII) 5a

(XXVIII) 5p

Vll

PART-2

BENZQTHIAZEPINES :

Benzothiazepines are claimed to exhibit a wide spectrum

of pharmacological activities as tranquilizing, antibacterial,

neurolectic, anticonvulsive, antidepressant etc. The survey

of literature revealed that no attempt has been made to pre

pare steroidal benzothiazepines in stigmastane series. Hence

with a view of synthesizing benzothiazepines in the steroidal

systems we carried out the reaction of some of the easily

accessible a,p-unsaturated ketones in the stigmastane series

such as 6-oxostigmast-4-en-3p-yl acetate (XXIX), 6-oxostigmast-

4-en-3^-yl propionate (XXX), 7-oxostigmast-5-ene (XXXl),

7-oxostigmasta-3,5-diene (XXXIl), 7-oxostigmast-5-en-3p-yl

chloride (XXXIII), 7-oxostigmast-5-en-3^-yl acetate (XXXIV),

7-oxostigmast-5-en-3p-yl propionate (XXXV)^ 3,6-dioxostigmast-

4-ene (XXXVI) with 2-amino thiophenol in absolute methanol.

(XXIX) (XXX)

R

OAc OPr

^10^21

— >

R

(XXXVII) OAc

(XXXVIII) OPr

9l0^2.

: viii :

CinH 10"21

R

(XXXI)

(XXXIV)

(XXXV)

H

OAc

OPr

9l0^2l

(XXXII)

->

9l3^2J

(XXXIX)

(XL)

(XLI)

R

H

OAc

OPr

C20H21

-> -4-

?10^21

(XLIII)

: ix :

^ 1 0 ^ 2 1

(XXXIII)

c 1 0 ^ : 1

(XLVI)

910^21 910^2.

(XXXVI) (XLVII)

: X :

PART-3

[A] STEROIDAL ARYLIDEhES :

Chritiansen et al. first reported the preparation

of 16-arylidine derivatives of androstanes and androstenes

which exhibit anabolic, androgenic, pituitary inhibiting,

coronary dilatory and antihypertensive activities. The

survey of literature revealed that no arylidene derivative

of the cholestane series is reported. For the synthesis of

such derivatives we selected some ketones in cholestane

series as 3-oxocholest-4-ene (XLVIIl),5,6p-dibromo-3-oxo-5a-

cholestane (XLIX), 3-oxocholesta-4,6-diene (L) and 3,6-dioxo-

cholest-4-ene (V). They were allowed to react with 4-N,N-

dimethylaminobenzaldehyde and the products obtained were

characterized on the basis of analytical and spectral data.

CQHJ_7 s' i?

(XLVIII) ( LI )

: XI :

^ 8 ^ 1 7

^8^17

(XLIX)

CsHl?

( L I I )

( L I I )

( L )

98^17 ^8^17

( V ) ( L I I I )

: xii :

[B] SOLID SURFACE REACTION ;

Epoxy ring opening reaction on solid phase has been

reported recently. In continuation and with the interest to

study the effect of silica gel as a solid phase, some easily

accessible steroidal epoxides such as 3p-hydroxy-5,6a-epoxy-

5a-cholestane (LIV) and 3p-hydroxy-5,6a-epoxy-5a-stigmastane

(LV^ were allowed to react with NaCl on silica gel at about

100 C. The results of the preliminary study are encouraging

with some unusual products as shown in the chart. R

->

R R

(LIV) CQH-^J

(LV) C;LOH21

(LVI)

(LIX)

CgH-]_y

^10^21

R

(LVII) C Q H ^ 7

(LX) ^10^^21

R

vLVIIl) CgH^7

^LXI) ^ 10- 21

: xiii :

PART-4

MASS SPECTRAL STUDIES CF BENZOTHIAZEPINES :

A survey of literature revealed that no systematic mass

spectral studies of steroidal benzothiazepines has been

reported. In the previous part we have described the prepa

ration of a number of benzothiazepines. These two events

prompted us to examine the mass spectra of several structurally

related steroidal benzothiazepines. These include 5a-cholestan

[4a,6-bc]-2',3'-dihydro-l*,5*-benzothiazepine (LXII),

5a-cholestan[4a,6-bc]-2*,3'-dihydro-l',5*-benzo'thiazepin-3p-yl

acetate (LXIII), 5a-cholestan[4a,6-bc]-2',3'-dihydro-l',5'-

benzothiazepin-3p-yl propionate (LXIV), 5a-stigmastan[4a,6-bc]-

2',3'-dihydro-l',5'-benzothiazepin-3p-yl acetate (XXX\ai),

5a-stigmastan[4a,6-bc]-2',3'-dihydro-l',5*-benzothiazepin-3p-yl

propionate (XXXVIII), 5a-cholestan[5,7-bc]-2',3'-dihydro-l* ,5'-

benzothiazepine (LXV), 5a-cholestan[5,7-bc]-2',3'-dihydro-l',

5*-benzothiazepin-3p-yl acetate (LXVI), 5a-cholestan[5,7-bc]-

2',3'-dihydro-l',5'-benzothiazepin-3p-yl chloride (LXVII),

5a-stigmastan[5,7-bcJ-2',3'-dihydro-l*,5'-benzothiazepine

(XXXIXJ, 5a-stigmastan-[5,7-bc]-2',3*-dihydro-l',5'-benzothia-

zepin-3^-yl acetate (XL), 5a-stigmast-3-en-[5,7-bc]-2',3'-

dihydro-l',5'-benzothiazepine (XLIV), N,S-phenylene-3a-thio-

3p-aminocholest-4-ene (LXVIII) and 6-oxo-5a-cholestan[2a,

4a-bc]-2',3',4',5«-tetrahydro-l',5'-benzothiazepine (LXIX).

XIV

It was anticipated that they will follow similar fragmentation

pattern thus offering a simple and effective method for their

characterization by mass spectrometry.

R

(LXII)

(UIII)

(UIV)

(xxxvii;

(XXXVIII)

X

H

AcO

PrO

AcO

Pro

R

^8^17

^8^17

%"l7

^10^21

^10^21

S \

{ (i-><v)

(LXVI)

(LXVII)

(XXXIX)

(XL)

/

3 X

H

AcO

CI

H

AcO

R

^8^17

S"l7

* 8"l7

^10"21

^10^21

910^21 CeHi/

(XLIV) (LX /III) (LXIX)

Cf)apttt~#nt

IMIDAZOPYRIDINES

Zlftovttml

The term imidazole was first introduced by Debus when

he discovered the compound for the first time in 1858. He

recognized the basic nature of the substance and established

the correct empirical composition as C^H.N- but he could not 2

propose a structural formula. It remained for Bambarger in

1893 to furnish the most convincing piece of evidence for the

structure of imidazole (ill) when he oxidized benzimidazole

(l) to 4,5-imidazole dicarboxylic acid (II) and by decarboxy

lation of this compound obtained, imidazole (III).

H H HOOC^ \ A .h

->

HOOC

(^^ ( I I ) ( I I I )

The term imidazole implies a five membered heterocyclic

ring system containing two ring nitrogens at 1,3 positions.

: 2 :

Imidazo [ l , 2 - a ] pyridine i s a comparatively new nucleus

but has accumulated many a l t e r n a t i v e names : 1,4-im.idazo-

pyr id ine (used by chemical a b s t r a c t s from 1917 to 1936),

pyr imidazole-pyr id ino ( l ' : 2 ' - 1:2) g lyoxa l ine , 3a-azaindole,

9-azaindolenine , 1,3-a-diazaindene and 3 ,7-a-d iaza indene . Most 3

commonly used numbering system IV i s as follows :

^^^ o 5

(IV) (V)

But a numbering system V slightly different from that

above was suggested by Tschitschibabin and is still encountered

m some of Russian papers .

5 In 1925 Tschitschibabin prepared VII by treating

2-aminopyridine (VI) with bromoacetaldehyde in a sealed tube

at 150-200 , However, these drastic conditions were not

necessary, and high yields of VII were obtained by treating

VI with chloro or bromoacetaldehyde and sodium bicarbonate in

aqueous alcoholic solution.

+ BrCH2CH0 ->

(VI) (VII)

• 3 •

Pure VII is a colorless liquid with an odour similar tc

that of other cyclic nitrogen bases, which turns dark upon

exposure to light and air. Imidazo[l,2-a]pyridine (VII) mi;nt

reasonaoly be expected to behave as an aromatic system. Reso

nance forms of type Vila and (especially) Vllb probably make

the major contributions to the resonance hybrid, with lesser

contributions from forms not involving an intact pyridinium

ring.

+

(Vila) (VII)

The r e a c t i o n of VI with chloroacetone yielded a methyl 7

homolog of VII which, Tschi tschibabin decided, was the 2-methyl

isomer. The r e a c t i o n of VI with a-halocarbonyl compound could

lead e i t h e r to 2 - or 3 - subs t i tu t ed imidazo[ l ,2 -a ]pyr id ine via

in termedia tes r e s p e c t i v e l y of type VII I or IX. Considerable 7

evidence was available that the ring nitrogen of VI was the

site of attack by alkyl, benzyl and phenacyl halides, although

acyl halides react only with the amino group.

L '/j + RCCH2X

(VI)

V'

N\ CH2CR

->

(VIII)^" " •- (Villa)

0' R

(IX) (iXa)

• 4 •

The 2-phenylimiciazo[l,2-a]pyridine (XI) was obtained'

from the reaction of VI with dypnone (X).

^ / ^ 6 " 5

r "

k^^N + HC ^ ^ ^ CH=CH-C5H5

^

CH-

(VI) (X) \k

)

CH, HC1/140°

(XI)

There is thus little doubt that product of this general

reaction are 2-substituted imidazo[l,2-a]pyridine. A slight

modification of this synthesis was introduced by Takahashi 9

and Shibasaki who replaced the customary a-halocarbonyl

compound by methyl-l,2-dichloroethylether.

r Ijl + CH3OCHCICH2CI

(XII) (XIII)

The reaction of a-aminonicotine (XIV) with bromopyruvic

ester (XV) gave 7-( l-,-nethyl-2-pyroliGyl)-2 (or 3) carDetho<y-

10 pyrimidazole (XVI)

+ BrCH2C0C02C2H5

2

(XIV) (XV)

H^C—N

' OS v^^V^w "• »i ""i (XVI)

The reaction of 2-bromocyclopentanone (XVIl) with

2-aminopyridine yielded a solid product. This product was

first thought by Reitmann to have structure XVIII but he

12 later favoured the more reasonable structure XIX.

0

(VI)

2 ^

(XVII)

- ^ >

• ^

(XVIII)

: 6 :

13 Paudler and Blewitt prepared many substixuted

imidazopyridine derivatives eg. XXI, XXIII by ta.<ir.g substi

tuted 2-aminopyridines(XX, XXII) and halocarbonyl cor.pounds.

+ CICH2CHO N1/)

(XX)

CH3

(XXI)

H, ( 'Jj + CICH2CHO

CH-

(XXII)

CH-

(XXIII)

14 Dubey and Ratnam synthesized imidazo-(b)-pyridines

(XXV) by treatment of 2,3-pyridinediamine (XXP/a) and its

5-bromo derivative (XXIVb) with carboxylic acid in presence

of polyphosphoric acid.

H

CH3CCX)H "' Xjr,")-*" (XXIV)

X

a = H

o = Br

(XXV)

a =

b =

X

H

Br

• 7 •

2H-Pyr ido[ l ,2-a]pyr imidin-2-ones (XXVII) were prepared 15

by reaction of Ph-C = C-CO„Et with 2-aminopyridines (XX /I)

+ Ph-C=C-CO Et

N

Ph

(XXVII)

R = H, Me, CI, Br, NH^

MeC0CHMeC02Et on treatment with 2-amino-6-methoxy-

pyridine (XXVIII) in presence of polyphosphoric acid and POCl^

gave pyridoLl,2-a]pyrimidine tXXIX) which has analgesic

property

^^^^ II I

+ CH -C-CH-COOEt-

H^CCr^ N^^NH.

(XXVIII)

17

N Me

(X:H_ 0 Me

3

(XXIX)

In 1982, Hand and Paudler gave the mechanism of the

reaction of 2-haloketones with 2-aminopyridine. From the data

they established that displacement of halogen is the slow step

in the reaction. They proposed a mechanism as shown in the

following scheme.

: e :

slow NH.

0 ^^

+N->^Ar

fast

The reaction of 2-aininopyridine with Et02CCH2COhRR• (R

and R« are the same or different C^_j alkyl or NRR' = 1-pyrro-

lidinyl morpholino) gave 4-(dialkylamino)-2H-pyridoLl»2-a]

pyrimidin-2-ones accompained by some 2-(dialkylamino)-2H-

pyrido[l,2-a]pyrimidin-4-ones. A mixture of 2-aminopyridir.e,

Et02CCH2C0NMe2 and POCl- in dichloromethane was refluxed to

give XXX and XXXI 18

Me /

+ Et02CCH2CON^ Me

(VI) MeMe

(XXX)

Me

y

(XXXI)

4-(MeS02) C^H^COCHBrMe (XXXIl) when stirred with 2-ami.-.o-

pyridine in P(0) (NMe2}3 at 40-50° gave 2-phenylimidazo[1,2-a]

pyridine derivative (XXXIIl) which is useful as antiinflamma

tory agent 19

: 9 :

^ ^ ^

. \ + Br

N-^ NH2 ^ ? " ^ Me

.S02Me

(VI) (XXXII)

CH„

(xxxii:)

S02Me

P y r i d o [ l ' , 2 ' : l , 2 ] p y r i m i d o [ 4 , 5 - b ] a c r i d i n e - 7 , 1 5 - d i o n e

(XXXV) was p r e p a r e d by c y c l i z a t i o n of a c r i d o n e (XXXP/) with

2 - a m i n o p y r i d i n e , fo l lowed by d e h y d r a t i o n 20

Benzylated 2-amino-3-hydroxypyridine (XXXVI) was cyclo-

condensed with ClCH2C0Me to give 8-benzyloxy-2-methylimidazo

[1,2-a]pyridine (XXXVIl), which shows antiulcer property

^^\^0CH2Ph ClCH2C0Me ^

0CH2Ph

Me

(XXXVI) (XXXVIl)

: 10

Biniecki and Madrzejewska synthesized 2H-pyrido[1,2-aj-

3,4-dihydro-3-hydroxypyrimidine (XXXVIII), 2H-pyrido[l,2-aj-3,

4-dihydropyrimidinone (XXXIX) as shown below.

(vi;

N - ^ M . HBr

:lCH2CH(0H)CH2Br

N .HBr

23

(XXXIX)

Alcaide et al."^" reported the synthesis of 2,2-diphenyl-

imidazoLl,2-a]pyridin-3-one (XLIl) by the reaction of 2-amino-

pyridine (VI) and benzil (XL) and confirmed the structure

XLII on the basis of i.r, data and single X-ray crystal

analysis. The same compound was earlier synthesized by SOKOV

who had reported it to be fairly unstable.

24

Ph-C-C-Ph

N- NH. ->

0

(XL) (VI) (XLI) (XLII)

1.'. :

25 Joshi et al. prepared 2(p-fluorophenyl)-3-phenylazo-

imidazo[l,2-a]pyridine (XLIV) by treating 2-aminopyridine with

a-oxo-N-phenyl-a-(4-fluorophenyl)ethane hydrazonoyl bromide

(XLIII). Absence of >C=0 and >N-H absorption bancs in IR

spectra indicated complete cyclization of XLIII into XLIV.

H I

— C- N-N

^r

(XLIII) (VI) (XLIV)

A m i x t u r e of 2 - c h l o r o n i c o t i n o y l c h l o r i d e (XLV) and

2 - - a m i n o p y r i d i n e i n t o l u e n e was h e a t e d t o g i v e p y r i d o [ 2 , 3 - d ]

p y r i m i d i o n e (XLVl) which shows d i u r e t i c p r o p e r t y .

N " CI N" NH^

(XLV) (VI ) (XLVI)

: 12 :

The p repara t ion of 8-hyc3roxyimidazo[l,2-a]pyridine

(XLVIIIj was c a r r i e d out by the r e a c t i o n of 2-amino-3-hydroxy-

pyr id ine (XLVII) with chloroaceta ldehyae in aosolute e thyl 27

alcohol under reflux for 12 hours

+ CICH2CHO

OH

,N-

N

//

(XLVII) (XLVIII)

A mixture of 3-bromoacetyl pyridine (XLIX) 2-amino-4-

hydroxy-6-methyl pyridine (L) and DMF was heated at 125^for

2 hours to give LI, which is useful as antiulcer agent and

28 blood platlet aggregation inhibitors

(XLIX) (L) (LI)

George and Allen prepared LIII by the cyclocondensation

of 2-amino-5-methylpyridine (XX) with p-BrCH^COC^H CO Et (LII)

: 13 :

subsequent hydride reduct ion, a c e t y l a t i o n , dimethylaminometnyla-

t i o n , q u a t e r n i z a t i o n with Mel, cyanat ion with KCN, hydrolysis

of the r e s u l t i n g c a r b o n i t r i l e , amidation with dimethylamine and

h y d r o l y s i s . The compound (LI I I ) i s repor ted to be useful as

29 sedative and anticonvulsant

COOEt

CCX:H2Br

N^^NH.

CH2OH

CH2C0NMe2

(LII) (XX) (LIII)

Heating of an equimolar solution of 1,2-dibromoethane and

2-aminopyridine (Vl) in dry acetonitrile at 100-110 C for ^3

hours gave in high yield, an acetone insoluble colourless

crystalline solid compound (LIV), which was converted into

2,3-dihydroimidazo[l,2-a]pyridine (LV) by treatment with base 30

N-

+ Br(CH2)2Br —>

NH^

base

ci-(VI) (LIV) (LV)

Bernath et al.^^ tried to prepare some 2-a2apyracidones,

a novel type of heterocycles, few of which have proved to

display significant analgesic and antiasthmatic properties.

: 14 :

They prepared 9-methyl-i,2,3,4-tetrahydro-ll-H dipyrido[1,2-a:

4,3-d]pyrimidin-ll-one (LVIl) and its N-benzyl derivative (LIX;

by the cyclization of 3-methoxycarbonyl-4-piperidone (LVI)

and its N-benzylderivative (LVIII) with 2-amino-6-methylpyridine

(XX) in presence of polyphosphoric acid.

R N

H2N

CH-

COOMe

0

(LVI) H

(LVIII) CH2Ph

R

(XX) (LVII) H

(LIX) CH2Ph

George et al. prepared 2-(4-methylphenyl)-6-(trifluo-

romethyl)imidazo[l,2-a]pyridine (LXI) by cyclocondensation of

5-(trifluoromethyl)-2-aminopyridine with a-bromo-4-methyl

acetophenone.

H3C-<Q^LcH

(LX) (LXI)

p-Hydroxyacetophenone was alkylated with Cl(CH„)„Br to

give 4-(3'-chloropropyloxy)acetophenone. This was cycla-

condensed witn 2-amino-3-methylpyridine to give 2-[4-(3'-chloro-

p r o p y l o x y ) p h e n y l ] - 8 - m e t h y l i m i d a z o [ l , 2 - a j p y r i d i n 9 (LXI l ) , t n e

33 d e r i v a t i v e s of which a r e used as l o c a l a n a e s t h e t i c

0

H3C-C-A' y - o ( c H ^ ; i : ,-^=^"^^"3

2 ' J N' NH,

C(C-.^)^C1

(LXII)

A mix ture of 2 - a m i n o p y r i d i n e and S-bromo- l -pheny lprcpane-

1 ,2-d ione in e t h a n o l was r e f l u x e d f o r 2 hours t o g ive LXIII, 34

which o r a l l y i n h i b i t e d AcOH-induced pa in .

O O II M

Ph-C-C-CH2Br +

(LXIII )

35 Catsoulacos and Souli reported that 3^-acetoxy-i6a-

bromo-5a-androstan-17-one (LXIV) and its 5-ene derivative

(LXV) react with 2-amino-4-methyIpyridine in xylene to afford

the corresponding imidazopyridine derivatives LXVI and UC.'ll

respectively.

. 16 :

-^

AcO

(LXV) (LXVII)

Condensation of 2-amino-4-methylpyridine with 21-bromo-

3^-hydroxy-5-pregnen-20-one (LXVIII) gave the 3^-hydroxy-5-

pregneno[20,21:2',3«]methyl-7«-imidazo[l«,2*-a]pyridine (LXIX)

in 43? yield 35

N " NHo H'

(LXVIII) (LXIX)

: 17 :

Catsoulacos and Nikolaropoulos prepared 17^-acetoxy-

5a-androstan[2,3:2*,3']imidazo[l,2-a]pyridine (LXXI) by

condensation of 17p-acetoxy-5-bromo-5a-androstan-3-one (LXX)

with 2-aminopyridine derivative.

OAc OAc

(LXXI)

(Lxx; R = H, 6'-CH3, 7'-CH3,

8'-CH3

3-Aza-A-homo-4a-androsten[l6,17:2',3']imidazo[l,2-a]

pyridine (LXXIIl) was obtained by treating aminopyridine with

l6a-bromo-3-aza-A-homo-4a-androstene~4,17-dione (LXXII) .

.R

,o BJ^

(LXXII) (LXXIIl)

R = H, 6'-CH^, '^'-C^3' 8 ' - %

IS

Using starting material as 2a-bromo-3-oxo-13a-amino-13,

17-seco-5a-androstan-17-oic-13,17-lactam (LXXIV) and 2-a~ino-3(S

5-methyIpyridine, Catsoulacos et al. obtained the 17a-aza-

D-homo-5a-androstan[2,3:2',3']imidazo[l,2-a]-6'-methylpyridine

(LXXV).

(LXXIV; (LXXV)

Mutnsiiiion

Imidazoles have been recognized as important compounds

in the living organism, a few can be mentioned as very good

examples. L-Histidine, biotin, 5-aminoimidazole-4-carboxy-

amide, vitamin B-12, 2-nitroimidazole, e-rgothioneine etc.

Their therapeutic values have also been reported. This

attracted the attention of the synthetic chemists to prepare

such derivatives. Survey of the literature reveals that very

little attention * is given to the preparation of such

compounds in the steroidal series. This prompted us to study

the reaction of 2-aminopyridine with easily accessible a-bromo-

ketones and a,^-unsaturated ketones in the cholestane and

stigraastane series with the intention of preparing imidazoles.

The substrates used for the study are 5-bromo-6-oxo-5a-

cholestane (LXXVI), 6-oxocholest-4-ene (DOCVll), 5-bromo-6-oxo-

5a-cholestan-3^-yl acetate (LXXVIIi;, 7a-bromo-6-oxo-5a-

cholestan-3^-yl acetate (LXXIX), 3,6-d ioxocholest-4-ene (LXXX),

5-bromo-6-oxo-5a-cholestan-3^-yl propionate (LXXXI), 5-bromo-

: 20 :

6-oxo-5a-s t igmastan-3p-yl a c e t a t e (LXXXII), 5-bromo-6-oxo-5a-

s t igmas tan-3^-y l propionate (LXXXIII). The p rod jc t s obtained

have been charac te r ized on the bas i s of t h e i r elemental analysis ,

s p e c t r a l p rope r t i e s and chemical t ransformat ions in a few cases.

98^17

R

(LXXVi; H Br H CQH^^

(laXVIIl) AcO Br H CgHj ^

(DCXIX) AcO H Br CgH^^

(LXXXI) Pro Br H CoH,^

(UCXXII) AcO Br H C-^QH^^ .

(LXXXIII) Pro Br H C^^H^^

^S^^l?

: 21 :

Reaction of 5-bromo-6-oxo-5a-cholestane ipCXVI) with 2-5mino-

pyr id ine ; 4H-Pvrido[2 " . 1* * ; 2 ' . 3* lovrimLdof '^ ' .5 ' . 6 ' ;^ t 5. 6]

cholestane (LXXXIV) :

37 5-Bromo-6-oxo-5a-cholestane (LXXVI) was allowed to

react with 2-aminopyridine under reflux temperature. Lfsual work

up of the reaction mixture gave one proauct as an oil along with

starting ketone. The oil 'A', analysed for ^32^40^0' indicated

the presence of aminopyridine moiety in the product.

CgH-|_y

or

(LXXXIV) (LXXXV)

In this reaction we may expect two products LXXXIV and

LXXXV on the basis of elemental analysis. The i.r. spectrun: ,38

of the compound showed bands at 3000, 1600 and 1580 cm" .

The bands at 3000 (aromatic C-H) and 16O0 being characteristic

of aromatic ring and 1580 characteristic of C=N further suppor

ted the presence of aminopyridine moiety. The n.m.r. signals

for the oil at d 7.6 and 7.3 as multiplets integrating for two

22 :

protons each could be assigned to pyximidine Kciety. A

triplet, observed at d 4.25 for one proton, ascribed to the

C4-proton (H-C4-N). A doublet observed at d 2.4 integrating

for two protons, could be assigned to allylic C7 methylene

protons. The signals for methyl groups were ooserved at d 0.93,

39 0.90, 0.83 and 0.7 . No other significant signal was observed.

The elemental analysis and i.r. and n.m.r. values could

not make a clear distinction between the two possible isomeric

structures (LXXXIV) and (LXXXV). However on tne basis of tne

proposed mechanism (Scheme-1) for the formation of the procuct

under the conditions, structure (LXXXIV) is preferred over its

isomer (LXXXV).

Therefore, the oil can best be formulated as 4H-Pyrido

[ 2 ' M ' • :2',3']pyrimido[4',5',6':4,5,6]cholestane (LXXXIV).

The formation of compound (LXXXIV) from the brOiiioketone can be

explained by considering that initially dehydrooromination gave

6-oxocholest-4-ene (LXXVIl) which then reacts with aminopyridine

as shown in Scheme-1.

Scheme-1

: 23 :

-HBr Proton

shift -s>

Proton shift

-H2O -^

(LXXXIV)

: 24 ;

The structure (LXOCIV), for the oil and the mechanism prooosed,

find support from the fact that the a,p-unsaturatec ketone

(LXXVII) when allowed to react with 2-aminopyridine gave the

compound which was identical in all respects to the oil sample

obtained from the a-bromoketone (LXXVI).

Reaction of 5-bromo-6-oxo-5a-cholestan-30-vl acetate (LXy/IIl)

with 2-aminoDyridine :

41 / a-Bromoketone (LXXVIII; on reaction with 2-aroinopyridine,

usual work up and column chromatography over silica gel,

afforded six solids with m.p. 90°, 125°, 142°, 124°, 110° and

152°C.

?8"l7

(LXXVIII)

(LXXXVI)

AcO

(LXXXVII) (LXXIX;

: 2D :

(LXXXVIII)

(XC), 5a (XCI) 55

Characterization of the compound with m.p. 90 as 6**-H

PvridoL2'*.1*';2*,3'lpvrimido[4*,5'.6';4.5.6]cholestan-5-one

(LXXXVI) :

The compound m.p. 90 was analysed for 022^45*^^2*

Presence of two nitrogen indicated the presence of amino-

pyridine moiety in the product.

AcO

(XCII)

AcO

(xciv; (LXXXVI)

: 26 :

Ne may expect four products LXXXVI, XCIJ-XIIV on the

basis of earlier observations.

The i.r. spectrum showed bands at 3C00 en * for aromatic

protons, 1675 for unsaturated carbonyl group, lo35 for carbc^-

carbon double bond and 1595 for carbon-nitrogen double bond.

Out of the four expected structures LXCC/I, XCII-XCIV

for the compound, XCII and XCIII were discaraec on the basis

of the composition observed. The i.r. also supported it ana

further suggested the presence of a,^-unsaturated carbonyl grouo.

thus XCIV was also discarded and structure LXXX"/! was preferred.

The n.m.r. spectrum showed multiplets at d 8.0 and 7.36

integrating for one and two protons respectively, assigned tc

C5'«-H and C4''-H, C3«'-H. A very complex signal from d 2.9

to 2.0 integrating for six protons could be ascribed to C2-H^,

C6"-H2 and C7-H2) in structure LXXXVI. Other ::ethyl groups

were observed at d 1.0, 0.9, 0.8 and 0,6. The i.r. and n.rr.r.

clearly showed the aosence of OAc group ana oresence of an

a,^-unsaturated carbonyl system. From the above data the

compouna could be characterized as 6*'-H pyrico^'2'', 1*' :2* ,3']

pyrimido[4',5',6':4,5,6]cholestan-3-one (IXCO.'i;. This

formulation found support b/ the fact that tie same comoounc

was obtained by the reaction of aminopyricire Nt-,h 3,o-dioxo-

chole5t-4-ene (LXXX}.

: 27 :

The formation of the coiTipound can be explained by

considering tnat the reaction proceeds via dehydrobromination

followed by the nucleophilic attack at the j3-carbon as shown

in Scheme-2.

The formation of 3-oxo group can be attributed to the

hydrolysis of acetate followed by oxidation at one or tne

other stage during the course of reaction. It can be suggested

that in the intermediate (XCIl) the carbon-carbon double bond

(CfT-C ) participated and helped in the removal of OAc.

CgHj_7

(LXXVIII)

-HBr ->

AcO

^ ^ p N H ,

(U)

Proton

shift AcO

: 28 :

Proto -HO —^—>

AcO

(xcii; (xciv)

Scheme-2

isom.

Identification of compound with m.p. 125 as 6-oxo-5a-

cholestan-33-vl acetate (LXXXVIt) :

The compound with m.p. 125° analysed for 20^^.003-

Absence of nitrogen excluded the possibility of aminopyridine

moiety. The compound was identified as 6-oxo-5a-cholestan-3p-

yl acetate (LXXX^/II) (reported"*^ m.p. 127-128°C), on the basis

of its spectral properties.

: 29 :

Identification of the compound .vith m.p. 142° as 7g-brorao-

6-oxo-5a-cholestan-3B-vl acetate (LXXDC) :

Tne compound with m.p, 142 C analysed for C2gH.yO-Br.

Absence of nitrogen shows the absence of aminopyridine moiety.

The compound was identified as 7a-bromo-6-oxo-5a-cholestan-

3^-yl acetate (LXXIX) (reported m.p. 143.8-146.8°C) on the

basis of its spectral properties. It is a simple case of

43 1,3 shift of bromine under reflux conditions as reported

earlier also.

Identification of the compound with m.p. 124° as 6-oxocholest5-

2.4-diene (LXXXVIII) :

The compound with m.p, 124°C was analysed for C -,H._0 anc

identified as 6-oxocholesta-2,4-diene (LXXXVIIi; (reportec'^

m.p. 129-130°C) on the basis of its spectral properties.

Identification of the compound with m.p. 110°C as 6-oxocholest-

4-en-33-vl acetate (LXXXIXJ :

Tne compound with m.p. 110°C, analysed for C^gH .0^,

identified as o-oxocholest-4-en-3^-yL acetate (XCI) 43 Q

(reported m.p. 110 C) on the basis of its spectral properties.

: 30 :

Characterization of the fraction with m.p. 152 C as mixture

of 5a-Dvrido[l*'.2" ;!'.2']imida2o[4'.5':6.7]cholestan-3g-vl

acetate (XC) and 53-pyrido[l''.2''t1'.2'Umida2o[4'.5';6.7]

chole5tan-3g-vl acetate (XCt) :

The substance with m.p. 152 was analysed for C^.H^^O N .

Presence of two nitrogen showed the possibility of amino-

pyridine moiety. In i.r. spectrum the bands at 3000 and

1650 cm~ can be ascribed to the aromatic moiety. Two more

bands at 1750 and 1730 cm" combined with a band at 1240 with

shoulder at 1220 cm" could be rationalized by considering it

to be a mixture of A/B trans and cis isomers (XC) and (XCI)

respectively. They could not be resolved under the experimental

conditions. The presence of C=N was indicated by a band at

1580 cm" . The n.m.r. spectrum showed two multiplets at d 8.08

and 7.93 integrating for two protons each (pyridine moiety).

Other multiplets at d 5.6 and 5.3 with Wl/2 = 5Hz and lOHz

respectively each integrating for half proton could be ascribed

to C3a-H equatorial (XCl) and C3a-H axial (XC). Two signals

for acetate methyl at d 2.06 and 1.93 further supported that

it was a mixture. Singlets at d 0.98, 0.93, 0.83 and 0.7 were

ascribed to other methyls protons.

By taking into account all the i.r. and n.m.r. data the

fraction m.p. 152°C can be characterized as the inseparable

mixture of 5a-pyrido[l'•,2'•:1',2•]imidazoL4',5':6,7]cholestan-

3^-yl acetate (XC) and its 5^-isomer (XCI).

: 31 :

The formation of XC and XCI can be expalined by

43 considering that bromine at C-5 in LXXVIII migrates to

C-7 followed by the reaction of 2-aminopyridine as shown in

Scheme-3. Which found support, as the same fraction was

obtained by the reaction of 2-aminopyridine and 7a-bromo-6-

oxo-5a-cholestan-3^-yl acetate (LXXIX),

AcO

(LXXIX)

AcO

H N ^ k - ^

AcO

-HoO • >

Acer

" 3 (XC) 5a-H

(XCI) 5^-H

Scheme-3

: 32 :

Reaction of 7g-bi omo-6-oxo-5g-chole5tan-3g-vl acetate (LXXIX)

•vith 2-aminopvrinine ; Inseparable mixture of 5a-DvridQ

I'l' ' .2' ' ;!' ,2' ]i:nida2o[4' .5' ;6,7lcholestan-3£~vl acetate (XC)

and 56-pvridoi"l' ' .2' ' ;1* «2* 1imlcia2or4', 5' ;6.^1cholestan-36-yl

acetate (XCI) :

7a-Bromo-6-oxo-5a-cholestan-3p-yl acetate (LXXIX) was

allowed to react with 2-aminopyridine. Lfsual work up of

reaction followed by chromatography affordec the fraction,

m.p. 152 C ano tne unreacted ketone. The suostance, m.p. 152*'

Was similar in all respects with the sample (last fraction)

obtained from the reaction of 2-aminopyridin6 with 5-bromo-6-

oxo-5a-cholestan-3f3-yl acetate (LXXVIII) and hence it is a

mixture of XC and XCI .

Reaction of 3.6-dioxocholest-4-ene (LXXX) with 2-aminopvridine;

6''H-Pyridol2*'.1**;2'.3*lDvrimidor4*.5'.6*;^.5.6lcholestan-3-

one (LXXXVI) :

44 3, 6-Dioxocr.olest-4-ene (LXXX; was alloived to react with

2-aminopyridine. On usual work up and column chromatography

over silica gel, the reaction mixture afforded only one fraction,

m.p. 90 along Aith the starting ketone (LXXX). The compound

with m.p, 90 was analysed for ^22^66^^'2' " ' con pound was

identical in all respects (i.r., n.m.r., m.p. and m.m.p.) with

tne fraction oDtained from 5-bromo-6-oxo-5a-cnolestan-3p-yl

: 33 :

acetate (first fraction)(LXXXVI). This further supported the

characterization as 6*'-H-pyrido[2**,1*':2*,3'jpyrimido

[4',5',6':4,5,6]cholestan-3-one (LXXXVi;.

Reaction of 5-bromo-6-oxo-5a-cholestan-3B-vl propionate

(LXXXl) with 2-aminopvridine ;

45 5-Bromo-6-oxo-5a-cholestan-3p-yl propionate CI-> XI)

Was allowed to react with 2-aminopyridine. Work up of the

reaction mixture in the usual manner followed by column chro

matography over silica gel afforded two fractions, with

ra.p. 132° and 202°C.

^8^17

(XCV)

(XCVI) (XC.'II)

3^ :

Identification of the compounc m,p. 132 as 6-oxocholest-^-eri-

3e-vl propionate (XCV) :

The compound, m.p. 132 was analysed for ^20^A8^3' ^"®

analysis, indicated this to be a simple case of dehydrobromi-

nation under the conditions. By considering spectral data,

t.l.c, m.p. and m.m.p. and in analogy with similar results

with the correspondingacetoxy derivative (LXXVIII) compound

was identified as 6-oxocholest-4-en-3p-yl propionate (XO/)

(reported , m.p. 132 ).

Characterization of the fraction m.o. 202° as inseparable

mixture of 5a-pvridoL1" . 2 " ;1'.2*limidazo[4'.5*;6.7lcholestan-

3g~vl propionate (XCVl) and 5g--pvrido[l" . 2 " 11* .2* limldazo

[4'.5't6.7lcholestan-3B-vl propionate (XCVII) :

The substance with m.p. 202 was analysed for C cHp.„0 N-.

Presence of two nitrogen showed the possibility of amino-

pyridine moiety. The i.r. spectrum showed bands at 3000, 1735,

1710, 1600 and 1572 cm~ , which indicated the presence of

aromatic protons, carbonyl group of ester linkage, carbon-

carbon double bonds and carbon-nitrogen double bond respectively,

The n.m.r. spectrum of the sample gave the peaks at d 8.06(d,

IH, C6"-H}, 7.46 (dd, IH, C4"-H), 6.65 (dd, IH, C5"-H),

6.42 (d, IH, 03''-H;, 5.25 (m, 1/2H, Wl/2 = 8Hz, C-3H,eq),

4.65 (m, 1/2H, Wl/2 = 18Hz, C-3H,ax), 2,97 (m, IH, C8-H), 2,27

: 35 :

O 0 'I il

(q, 2H, CH3CH2-C-O), 1.1 (t, 3h, CH3CH2-C-O), 0.9, 0.88, 0.85

and 0.7 (other nethyl protons). The banas tor the carbonyl

frequency in i.r. (1735 and 1710 cm" ) ana two multiplets for

1/2 protons each at d 4.65 and 5.25 can be rationalized on

the oasis of the discussion advanced in case of similar product

[(traction m.p. 152 ) (XC and XCl)] from the corresponding

acetoxy derivative (DCXVIII). Hence in analogy, this fraction

(m.p. 202°) can also be best characterized as a mixture of

5a-pyrido[l'',2'':1',2']imidazo[4',5':6,7]cholestan-3p-yl

propionate (XCVI) and 5p-pyrido[!•',2 " :1',2']imidazo[4«,5':

6,7]cholestan-3p-yl propionate (XCVIl).

Reaction of 5-bromo-6-oxo-5a-stiamastan-3B-yl acetate (LXXXIl)

with 2-aminopvridine :

Bromoketone (LXXXIl) was allowed to react with 2-amino-

pyriaine. Work up of the reaction mixture in the usual manner

followed by column chromatography over silica gel afforded

four fractions, a solid m.p. 112° and other two as noncrysta-

llizable oils 'B' and 'C along with oily mixture which coula

not be resolved further due to lack of quantity.

^10^21

AcO

->

AcO

AcO

(XCIX)

AcO

(CI)

(C)

(CII)

Icentitication of the compound m.p. 112 as 6-oxostiqma5t-4-

en-3e-vl acetate (XCVIII) :

The compouna with m.p, 112 was analysed for ^^-.H^QO^.

The analysis indicated this to be a simple case of dehydro-

bromination under the conditions. By consicering spectral

46 da ta , TLC , m.p. and m.m.p. and in analogy with s imilar

r e s u l t s with the corresponding c h o l e s t e r o l d e r i v a t i v e s the

; 37 :

compound, m.p. 112 was identified as 6-oxostigmast-4-ei-3p-yl

acetate (XCVIII, (reported"^^, m.p. 115°C).

Characterization of oil *B* as the inseperable mixture of

oa-hydroxv-5a-pvridori* * , 2 " ;1*,2']imidazo[4'.5't6.7]-4'.5'-

dihYdrostiqmastan-36-vl acetate (XCIXJ and 6a-hydroxy--58-

pyrido[l'',2'*:1'.2*]imidazo[4',5':6,7]-A*,5'-dihydrostigmastan-

36-yl acetate (C) :

The oil 'B* was analysed for ^26^^6^3^2' Presence of

two nitrogen showed the possibility of aminopyridine moiety.

The i.r. spectrum showed bands at 3350 (hydroxyl group;, 3000

Caromatic protons), 1730, 1720 (ester carbonyl group in XCIX

and C), 1600 (carbon-carbon double bonds), 1570 (carbon-

nitrogen double bond), 1240 cm"" (C-0 bond). The n.m.r.

spectrum gave the peaks at d 7.5 (m, 2H, 06''-H, C4"-H), 6.7

(m, 2H, C5"-H, C3'«-H), 5.5 (m, 1/2H, Wl/2 = 8Hz, C3-H, eq ,

(O), 4.96 (m, 1/2H, Wl/2 = 19Hz, C3-H, ax (XCIX)), 3.4 (s, IH, 0

-OH), 2.38 (d, IH, C7a-H), 2.1 and 2.0 (both s, 3H, ^3-^-0),

1.0, 0.9, 0.8b, 0.76, 0.66 (other methyl protons). Analogy

with the earlier discussions and two bands for the carbonyl

frequency in i.r. (1730 and 1720 cm~^), two multiplets for 1/2

proton each at 0 4.96 and 5.5 and a singlet at d 3.4 (O-H)

could best be rationalized if oil 'B' can be characterized as

the inseperable mixture of 6a-hydroxy-5a-pyrido[1'•,2'':1',2']

imidazo[4',5':6,7]-4',5'-dihydrostigmastan-3p-^yl acetate

(XCIX) and its 5^-isomer (C).

: 38 :

Characterization of oil *C' as the inseperabl'? mixture of

5a-Pvrido| 1' '.2*';1*.2']imidazoL4'.5';6,7lstiqmastan-3g-vl

acetate (CI) and 5g~Dvridori" . 2 " ; 1',2'limidazo[4\ 5';6. 7]

stiamastan-3g-yl acetate (Cll) :

The oil *C* was analysed for ^26^^4^2^2' Presence of

two nitrogen showed the presence of aminopyridine moiety.

The i.r. spectrum showed bands at 3000, 1730, 1720, 1600,

1570 and 1240 cm" which indicated the presence of aromatic

protons, carbonyl groups with ester linkage, carbon-carbon

double bonds and carbon nitrogen double bonds. The n.m.r.

spectrum of sample gave peaks at d 7.6 (m, 2H, 06*'-H, 04''-H),

6.75 (m, 2H, C5"-H, C3"-H), 5.79 (m, 1/2H, Wl/2 = 7Hz,

C3-H, eq.), 4.65 (m, l/2H, Wl/2 = 17Hz, C3-H, ax), 2.35 (m, IH,

C8-H), 2.03 and 2.0 (both s, 3H, CH^-b-O-), 1.0, 0.95, 0.85,

0.8, 0.76, 0.69 (other methyl protons). As reported earlier

for such derivatives in cholestane series, two bands for

carbonyl frequency in i.r. (1730 and 1720 cm"-"") and two multi-

plets for 1/2 proton each at d 5.79 and 4.65 could be rationa-

lizea by considering the oil 'C as a mixture of 5a-pyrido

[l",2'•:l',2']imidazo[4',5':6,7jstignastan-3^-yl acetate (CI)

and 5^-pyriaoLl",2":l',2'jimidazor4',5':6,7]stigmastan-3^-yl

acetate (CII).

The formation of the two mixtures (XCIX and C) and (CI

and CU) can be explained according to the 5cheme-3 as shown

: 39 :

earlier for the formation of (XC and XCl) wnere only the

dehydrated product is isolated.

Reaction of 5-bromo-6-oxo-5a-stiqmastan-33-yl propionate

(LXXXIII) with 2-aminoDvridine :

5-Bromo-6-oxo-5a-stigmastan-3p-yl propionate (LXXXIII)

was allowed to react with 2-aminopyridine. ".Vork up of the

reaction mixture in the usual manner followec by column

chromatography over silica gel afforded three fractions,

m.p. 135 and other two as ncncrystallizable oils 'D' and 'E'.

^10^21

Pro

(LXXXIII)

Pro

(civ; (cv;

icvi) (evil)

: 40 :

Characterization of the compound. m,p. 135 as 6-3XostiQmast-

4-en-3g-vl propionate (CIII) :

The compound with m.p. 135 was analysed for 32^52*^3*

Absence of nitrogen excluded the possibility of aminopyridine

moiety. Negative Beilstein test indicated that dehydrobromi-

nation has occurred. The i.r. spectrum of the compound showed

bands at 1735, 1680 cm" which indicated two carbonyl groups

as ester one and other conjugated with double bond. Broad band

at 1630 also showed the presence of double bond. The n.m.r.

spectrum of the compound showed peaks at d 6.03 as doublet for

one vinylic proton. A quartet at d 2.27 for 2 protons and

triplet at d 1.11 for 3 protons assigned to five protons of

propionate moiety. Five singlets for other methyl protons

were observed at d 1.0, 0.9, 0.85, 0.76 and 0.69.

On the basis of spectral and analytical data the compound

m.p. 135 can be formulated as 6-oxostigmast-4-en-3^-yl

propionate (CIII) which found support from the fact that

similar product was obtained in other cases as discussed

earlier. The bromoketone CLXXXIII) when treated with pyridine

also gave the same compound hence further supporting its

characterization.

Cnaracterization nf oil 'P' as the inseperable mixture of

6a-hydroxv-5a-pvridori".2":l'.2'1imida2o[4'.5';6.7l-4'.5'-

dihydrostlqma5tan-3g-yl propionate (CIV) and 6a-hvdroxv-5B-

: 41 :

Dvridoi 1' ' . 2 " ; 1' .2' limidazo[4' .5' ;6.7l-4' .5'-dihvcro-

stiqmdStan-33-vl propionate (CV );

The oil 'D* was analysed for C3yH g02N2(M"*"* 678).

Presence of two nitrogen showed the presence of aminopyriaine

moiety. The i.r. spectrum showed bands at 3350, 3000, 1735,

1725, 1620, 1572, 1240 which indicated the presence of hyaroxyl

group, aromatic moiety, carbonyl groups with ester linkage,

carbon-carbon double bonds and carbon-nitrogen aouble bond

respectively. The n.m.r. spectrum gave peaks at d 7.8 (m,

2H, C6"-H, C4"-H), 6.75 (m, 2H, 05''-H, C3"-H), 5.45 (m,

1/2H, Wl/2 = 8Hz, C3-H, eq), 4.95 (m, 1/2H, Wl/2 = 17Hz,

C3-H, ax), 3.41 (s, IH, -OH), 2.35 (d, IH, C7-H), 2.27 (q, 2.4, 0 O

CH3CH2C-O . ) , 1.2 (t, 3H, CH3CH2C-O ), 1.02, 0.91, 0.85, 0.75,

0.65 (other methyl protons).

Presence of two ester carbonyl (1735 and 1725 cm"-"-) and

two multiplets for 1/2 proton each at d 5.45 and 4.95 can

be compared with the data for similar product (fraction oil

•B«) from LXXXII. Hence this fraction oil 'D' can characteri

zed as a mixture of 6a-hydroxy-5a-pyrido[1'•,2'':1•,2']

imidazo[4',5':6,7j-4',5'-dihydrostigmastan-3^-yl propionate

(CIV) and 6a-hydroxy-5^-pyrido[l",2":l',2']imida2o[4',5':

6,7]-4',5'-dihydrostigmastan-3p-yl propionate (CV).

: 42 :

Characterl :ation of the oil 'E* as inseoerable mixture of

5a-Pvricioi 1' ' .2' ' ; 1' .2' 1imiciazof4' ,5' ; 6.7'stior .astan-33-vl

nroDionate (CVl) and 5g-pyrido[ 1" , 2 ' ' ; 1'. 2 ' ]i.T.idazo[4'. 5« ;

6,7]stiqmastan-3g-yl propionate (CVIl) :

The oil 'E' analysed for C^yH^^O N (W^* 660). Presence

of two nitrogen showed the possibility of aminopyridine

moiety. The i.r. spectrum showed bands at 30CX), 1735, 1723,

1600, 1572 which indicated the presence of aromatic protons,

two carbonyl groups, carbon-carbon double bonds and carbon

nitrogen double bond respectively. The n.m.r. spectrum of the

oil gave peaks at d 8.1 (m, 2H, C6"-H, C4''-H), 7.5 (m, 2H,

C5"-H, C3"-H), 5.25 (m, 1/2H, Wl/2 = 7H2, C3-H,eq), 4.7 (m,

1/2H, Wl/2 = 17Hz, C3-H,ax;,2.9 (m, IH, CS-H), 2.3 (q, 2H, O O

CH3CH2-C-O), 1.12 (t, 3H, CH3-CH2-C-O), 1.01, 0.95, 0.87, 0.77,

0.67 (other methyl protons). The bands for carbonyl groups

and two peaks for 1/2H at d 4.7 and 5.25 could also be

rationalized by considering oil •£' as isomeric mixture of

5a-pyrido[l",2":l',2']imida2o[4',5':6,7]stigmastan-3p-yl

propionate (CVI) and 5^-pyrido[l'•,2'•:1',2']imidazo[4',5':

6,7jstigmastan-3^-yl propionate (CVII), which was similar to

the observation made in case of oil 'C from the ketone

(uxxii;.

experimental

All melting points were observed on a KofX^T hot block

and axe uncorrected. I.R. spectra were oozained in KBr witr.

a Perkin-Elmer 237 spectrophotometer. I.R. values are given

in cm""*". •'•H-N.M.R., spectra were run in CDCI3 on a Varian

A-60D instrument with Me^Si as the internal standard and its

values are given in ppm (d) (s, singlet; or, broad; mc,

multiple centered at; d, doublet and dd, doublet of a doublet).

The N-H signals disappeared on addition of D^O witn no

significant change in other parts of spectra. Mass spectra

were measured on JMS-3CX) spectrometer. The values of fragment

ions from various compounds are given, the values in parentheses

of the relative abundance {%) of the peaks .vith resoect to t.ie

base peak as 1CX)%. Thin layer chromatograpnic {TIC) plates

were coated with silica gel and sprayed v.i-n 20% aqjeous

solution of perchloric acid. Silica gel (20 g) was used for

each gram of the material to be separatee in column chromato

graphy. Petroleum ether refers to a fraction of b.o. 60-8C^C.

: 44 :

Cholest-5-en-3l3-vl chloride :

Freshly purified thionyl chloride (40 ml) was added

gradually to cholesterol (50 g) at room temperature. A

vigorous reaction ensued with the evolution of gaseous

products. When the reaction slackened, the mixture was gently

heated at a temperature 50-60° on a water batn for one hour

and then poured into water with stirring. The yellow solid

thus obtained was filtered under suction and washed several

times with ice cold water and air dried. Recrystallization

from acetone gave cholest-5-en-3p-yl chloride^(45 g), m.p.

95-96° (reported^^, m.p. 96-97°C).

Cholest-5-ene :

Cholest-5-en-3^-yl chloride (10 g) was dissolved in warm

amyl alcohol (230 ml) and sodium metal (20 g) was added to

the solution with continuous stirring over a period of 8 hours.

The reaction mixture was warmed occassionally. When all the

sodium metal was dissolved, the reaction mixture was poured

into water acidified with hydrochloric acid and then allowec

to stand overnight. A white crystalline solid thus obtained

was filtered under suction and washed thoroughly with water

and air driea. The crude material was recrystallized from

acetone to provide cholest-5-ene as cubes,(8.3 g), m.p. 94°

(reported" - , m.p. 95°C).

: 45 :

6-Nitrocholest-5-ene :

A suspension of finely powdered cholest-5-ene (6 g) ir.

glacial acetic acid (50 ml^ was vigorously stirred at room

temperature and treated with nitric acid (15 ml, d : 1,5)

followed by addition of sodium nitrite (3 g) over a period cf

one hour. The reaction mixture was poured into cold water

anc the yellow product thus obtained was extracted with ether.

The ethereal layer was washed successively with water, sodi-:n

bicarbonate (10%) (until the washing were pink) and again with

water and dried over anhydrous sodium sulphate. Removal of

the solvent provided the desired compound as an oil which was

crystallized from ethanol as leaf lets,(4.5 g) m.p. 119-120

(reported"^^, m.p. 120-121°C).

6-Oxo-5a-cholestane :

6-Nitrocholest-5-ene (6 g) was dissolved in warm glacial

acetic acid (120 ml) and Zn-dust (12 g) was gradually added

witn sna<ing. The mixture was heated under reflux for four

hours alia water (12 ml) was added during the course of reaction,

Zn-cjst (unreacted) was removed by filtration and the filtrate

was diluted with water, 6-oxo-5a-cholestane crystallized out

as tnin plates was recrystallized from ethanol^(3.5 gm),

m.p. 96-98° (reported^^, m.p. 98-100°C).

5-Bromo-6-o: o-5a-cholestane (LXXVIj :

6-Oxo-ba-cholestane (8 g) was xixed with acetic acia

(18 ml), ether (91 ml} and cooled to 0 C. Bromine solution

(4.1 g of bromine in 58 ml of acetic acia) was adcec to it

slowly. Few drops of hydrobromic acid were added to catalyse

the reaction. Decolourisation proceeded rapidly arc a

crystalline material started seperating after the addition of

approximately half of the bromine solution. Bromine solution

was added till the colour persisted. The ether was re.-n.ovea

under reduced pressure and dried bromo ketone (LX>r/l)

collected and was recrystallized from petroleum etherj(3.6 g)

m.p. 102° (reported^^, m.p. 101-102°C).

Reaction of 5-bromo-6-oxo-5a-cholestane (LXXVl) with 2-amino-

Dvricine ; 4H-Pvridor2''.1" t2'.3*]Dvrimido[4'.5'.6';4,5. 6]

cholestane (LXXXIV) :

The bromo ketone (LXXVI) (2 g) was aissolved in xylene

(40 ml) and to this was addec 2-aminopyridine (.500 aig; and the

mixture was refluxed for six hours. After filtration the

solvent was evaporated under reduced pressure. The residue was

extracted with ether and the solution washed several times with

water and dried over anhydrous sodium sulohate. Evaporation

of the solvent afforded the compound (LXXXIV) as an oil 'A'

(1.5 g) rj = 1.6, Rf 0.41.

: 47 :

, 3000 (aromatic), 1600 (C=C), 1580 (C=N) cm ^. y max.

d 7.6 (2H, m, C6"-H and C4"-H), 7.3 (2H, m, CD'«-H and

C3"-H), 4.25 (IH, t, J = 7Hz, C4-Hp), 2.4 (2H, d, C7-K2),

0.93, 0.90, 0.83, 0.7 (methyl protons).

Analysis Found : C, 83.3 ; H, 10.6; N, 6.1^

^32^48^2 ^^q^i^^s • » 83.41; H, 10.50; N, 6.08^.

6-0xocholest-4-ene (DCXVIl) :

A solution of 5-bromo-6-oxo-5a-cholestane (LXXVI) (5 g)

in pyridine (50 ml) was heated under reflux for eight hours

under anhydrous conditions. The mixture was diluted with ice

cooled water and extracted with ether. The ethereal solution

was washed with water, dilute hydrochloric acid, sodium bicar

bonate (5%) and water and dried over anhydrous sodium sulphate.

Evaporation of the solvent gave LXXVII as an oil which was

crystallized from methanol^(2.7 g), m.p. 108° (reported ,

m.p. 108-109°C).

Reaction of 6-oxocholest-4-ene (LXXVIl) with 2-aminopvridine :

4H-Pvrido[2* * . 1 " t2*.3'1pvrimido[4*.5'.6*;4.5.6lcholestane

(LXXXIV) :

The ketone (LXXVIl) (500 mg) was dissolved in xylene

(10 ml) and to this was added 2-aminopyridine (100 mg). The

mixture was refluxed for six hours. The reaction \Nas monitored

hourly by TLC. The starting compound was not completely

: 43 :

changed into the product. After filtration the solvent was

evaporated uncer reduced pressure. The residue was extracted

with ether and solution washed several tines with water arc

dried over anhydrous sodium sulphate. Evaporation of the

solvent gave an oil which on column chromatography over silica

gel gave two fractions. Elution with a mixture of petroleum

ether and ether (20:1) gave the oil (DCXXI/) (100 mg) whicn

was not crystallized after several attempts. The oil was

similar in all respects with the sample obtained from the

reaction of 2-aminopyridine with 5-bromo-6-oxo-5a-cholestane

(DOCVI).

Further elution with petroleum ether and ether (10:1)

provided the unreacted ketone (LXX'/II)whicn was crystallized

from methanol,(200 mg), m.p. 108° (reported"** , m.p. 108-109°C).

Cholest-5-en-3g-vl acetate :

A mixture of cholesterol (50 g), pyriaine (75 ml) and

acetic anhydriae (50 ml) was heateo on a steam bath for two

hours. The resulting brown solution was poured onto crushed

ice-water mixture with stirring. A light brown solid was

obtained which was filtered under suction and washed several

times with water until free from pyridine and air dried.

The crude product on recrystallization from acetone gave the

pure acetate, (45 g), m.p. 114-115° (reported"*^, m.p. 116°C).

: 49 :

5-Bromo-6g-hvciroxv-5a-cholestan-3g-vl acetate :

Cholest-5-en-3^-yl acetate (12 g) was dissolved in ether

(2CX) ml) and cooled to 0°C to this was acded perchloric acic

(1.6 ml) and N-bromosuccinimide (9.6 g). The mixture was

then stirred at room temperature for two hours. The reaction

mixture was extracted with ether, washed with water and cried

over anhydrous sodium sulphate. Evaporation of the solvent

gave a solid which was recrystallized from petroleum ether to

give the bromohydridn^(8 g) m.p. 162 (reported , m.p. 162 Z).

5-Bromo-6-oxo-5a-cholestan-36-yl acetate (LXXVIII) :

To a solution of 5-bromo-6^-hydroxy-5a-cholestan-3^-yl

acetate (10 g) in acetone (300 ml), Jone's reagent (15 ml)

was added and the reaction mixture was stirred at 5-10 C for

two hours. Excess of chromic acid was destroyed by isopro-

panol and saturated solution of sodium acetate. The mixture

Was poured into water and the solid thus obtained was filtered,

air dried and recrystallized from methanol to give the pure

a-bromoketone (LXXVIIl), (8.5 g) m.p. 162-164° (reported"^-,

m.p. 162°C).

Reaction of 5-bromo-6-oxo-5a-cholestan-3g-yl acetate (LX>r/III}

with 2-aminoDyridine ; 6**-H-Pvrido[2''.1'*t2 *.3'Ipyrimiao

14'.5'.6';4.5.6lcholestan-3-one (LXXXVl). 6-oxo-5a-cholestan-

33-vl acetate (LXXXVIl). 7a-bromo-6-oxo-5a-cholestan-3g-yI

: 50

acetate (LXXIX). o-oxocho." est.i-2.4-aiene (LXCC/III), 6-oxo-

cholest-4-en-38-vl acetate (C(XXIX). 5a-pvricof1" .2 " ;1'.2'1

imidazoL4't^* ; 6. "7 jcholestan-3g-yl acetate (XC) and 5£-pvricio

[1'' . 2 " ;!'.2']ir.idazor4* .5';6.7]cholestan-3£-vl acetate (XCI)

a-Bromoketone (LXXVIIl) (2 g) was dissolved in xylene

(40 ml) and to this was added 2-aminopyridir.e (400 mg) ana

the mixture was refluxed for six hours. The reaction was

monitored by TLC. After the usual work up as described

earlier the oily residue (Ca 1.8 g) was chromatographed over

silica gel and gave six fractions. Elution with a mixture of

petroleum ether and ether (20:1) gave the compound (LXXXVI)

which was recrystallized from petroleum ether,(200 mg),

m.p. 90°C.

-)) ^^^ 3000(aromatic), 1675 (-C=C-C=0), 1635 (C=C), 1595 (C=N)

-1 cm

d 8 .0 (IH, m, C 5 " - H ) , 7.36 (2H, m, C 4 " - H and C 3 " - H ) ,

2 . 9 - 2 . 0 (6H, m, C 6 " - H 2 , C2-H2, C7-H2), 1.0, 0 . 9 , 0 . 3 ,

and 0 . 6 (otr.er methyl p r o t o n s ) .

A n a l y s i s Found : C, 80 .9 ; H, 9 . 8 ; N, 5 .8

^32^46°^2 ^^q^ i^e s : C, 80 .96 ; H, 9 . 7 6 ; N, 5.90%.

F u r t h e r e l u t i o n with pe t ro leum e t h e r and e t h e r (15 :1 )

gave LXXXVII which was r e c r y s t a l l i z e d from r . e thano l , (250 mg)

m.p. 127° ( r e p o r t e a ^ ^ , m.p. 127-128°C) .

: 51 :

0

; 1730 (C:-' -C-0), 1720 (C=0; , 1230 (acetate) cr."

d 4.58 (IH, .-n, C3-H, ;Vl/2 = l8Hz), 2.3 (3H, m, Cz-U,

C7-H2), 1.98 (3H, s, CH3CCO), 1.08, 0.9, 0.83, 0.75

(other me-hyl protons).

Analysis Founc : C, 78.3 ; H, 10.6

Calcd. for C25H48O3: C, 78.32; H, 10.68^.

Continuec elution with the same solvent system afforcea

.LXXIX which ^as recrystallized from methanol (350 nil),

m.p. 142° (repcrted^^, m.p. 143.8-146.8°C), positive Beilstein

test.

O

i^ ^ 1735 (c:-:^-C-0), 1710 (C=0), 1230 (acetate), 780 (C-3r)

- 1 cm

d 4 . 5 (IH, - , C3-H, Wl/2 = 17Hz), 4 . 1 (IH, br s , C7-Hp),

2 . 3 5 (IH, m, C8-H), 2 .0 (3H, s , CH3COO), 0 . 9 4 , 0 . 8 3 ,

0 . 8 , 0 . 7 1 ( o t h e r methyl p r o t o n s ) .

A n a l y s i s Found : C, 66 .5 ; H, 9 .1

Ca lcd . fo r

^ 9 ^ 4 7 ^ 3 ^ ^ • ^ ' 66 .52 ; H, 9 .04^ .

Continuec elution with the same solvent system (12:l)

afforded LXXX-.III which was recrystallized from methanol

(300 mg), m.p. 124° (reported'^^, m.p. 129-130°C).

: 52 :

i) 3030 (aroTiatic), 1665 (-C=C-C=0), 1620 CC=C) cm"' . max.

d 6.73 (IH, m, C2-H), 6.06 (2H, dd, C3-H, C4-H), 2.45

(2H, m, C7-H2), 2.3 (2H, m, CI-H2), 1.0, 0.93, 0.83

and 0.71 (other methyl protons).

Analysis Found : C, 84.7 ; H, 11.0

Calcd. for C27H^2° * ^' ^^'"^^'^ ^' 11'06^-

Further elution with a mixture of petroleum ether and

ether (10:1) provided the compound (LXOdX) which was

recrystallized from methanol (200 mg), m.p. 110 (reported ,

m.p. 110°C). 0

^ II _ 1

V 1730 (CH„C0), 1690, 1625 (-C=C-C=0), 1225 (acetate) cm ., rricix • o

d 5.93 (IH, br s, C4-H), 4.85 (IH, m, C3-Ha, Wl/2 = 16Hz'

2.2 (2H, m, C7-H2)» l.H, 1.0, 0.91 and 0.81 (other

methyl protons).

Analysis Found : C, ^s.e'; H, 10.4

Calcd. for C^^^^O^ : C, 78.68; H, 10.47%.

Eiuates from the same solvent (7:1) gave the mixture of

isomeric compounds (XC) and (XCI) which was crystallized

from methanol (200 mg), m.p. 152°C. 0

^max. ^ ^ ° (aromatic;, 1750, 1730 (CH3CO), 1650 (C=C), 1580

(C=N), 1240, 1220 (acetate) cm-^

: 53

d 8.08 (2H, m, C3"-H and C6''-H), 7.93 (2H, m, C4"-H and

C5"-h), 5.6 (1/2H, m, C3-Ha, eq. Wl/2 = 5Hz), 5.3 (:/2K,

m, C3-Ha, a:<., Wl/2 = lOHz;, 2.06 and 1.93 C3K, s, CH^ ::C0 J,

0.98, 0.93, 0.83, 0.7 (other methyl protons;.

Analysis Found : C, 78.6; K, 9.6; N, 5.3

34- 5o' 2 2 ^q^i^^s • C» 78.71; H, 9.71; N, 5.39%

Reaction of 7a-bromo-6--oxo-5a-cholestan-36-vl acetate (LXXIX)

with 2-aminopyriGine ; Inseparable mixture of 5Q-Dvrido[l''.

2* ' ;1'.2']imidazo[4'.5*:6.7]cholestan-3g-vl acetate (XC) a-.d

5a-pyrido[l«'.2" ;1*.2'limidazol4'.5';6.7lcholestan-3p-yl

acetate (XCI) :

The a-bromoketone (LXXIX) (500 mg) was dissolved in

xylene (10 ml) and to this was added 2-aminopyridine (100 rg)

and the mixture was refluxed for six hours. The reaction v.as

monitored by TLC. The starting bromoketone was not completely

changed into product even after continuous refluxing. After

filtration, solvent was evaporated under reduced pressure.

Tne residue was extracted with ether and washed several ti.res

with water and dried over anhydrous sodium sulphate. Evacc-

ration of the solvent gave an oil (Ca 400 mg) which on coluiin

cnrornatography over silica gel gave two fractions. Elution

with a mixture of petroleum ether and ether (20:1) affordec

unreocted ketone (LXXIX) which was crystallized from methanol,

: 54 :

(180 mg) z.,p. 1-12° (reported'^^, m.p. 1^3.8-146.8°C),

positive Eeilstein test.

Continued elution with same solvent system (7:1) gave

the mixture of isomeric compounds (XC) and (XCl) which was

crystallizec from methanol ,(110 mg), m.p. 152 C, anc was

found similar in all respects with the isomeric mixture

obtained from the reaction of 2-aminopyridine with 5-bromo-t:-

oxo-5a-chciestan-3p-yl acetate (last fraction) (XC and XCI).

.3g.5.6g-rrihyaroxy-5a-cholestane ;

A mixture of cholesterol (20 g) and formic acia (20 ml,

88%) was neated on a water bath at 70-80 C for 5 minutes and

then allo'iiec to attain room temperature. Hydrogen peroxide

(20 ml, 3C%) was added to the mixture and it was kept at ream

temperature for twelve hours with occasional shaking. Boiling

water (30C nl) was added to the mixture,allowed to attain raom

temperature when a white solid separated which was filterec

under suc-.ion and air dried. The solid was dissolved in

methanol [oCO ml) and the solution was heated with sodium

hydroxiae solution (20 ml, 25%) for ten minutes on a steam cath.

It was aciaified with hydrochloric acid and diluted with

boiling water (300 ml). The triol obtained on cooling was

collectec DV filtration under reduced pressure and recrysta-

llized from .T.etnanol,(l8 g), m.p. 237° (reported^^, m.p.

237-239°C..

55 :

3. 6-Dioxo-5-hvdroxy-5a-cholestane :

A suspension of 3^,5,6p-trihydroxy-5a-cholestane (5 g)

in acetone (200 ml} was cooled in an ice bath. Jone's

reagent (15 ml) was added gradually with stirring over a

period of thirty minutes. Water (200 ml) was added to the

reaction mixture and the precipitate thus obtained was collec'

tec by filtration under suction. The crude product was

subjected to column chromatography over silica gel (100 g).

Elution with chloroform gave the dione which was recrysta-

llized from methanol,(3.2 g), m.p. 237 (reported , m.p.

237-239°C).

3.6-Dioxocholest-4-ene (LXXX) :

A mixture of 3,6-dioxo-5-hydroxy-5a-cholestane (2 g),

dioxan (140 ml) and sulphuric acid (2 ml) was heated under

refljx for one hour. The solvent was removed under reduced

pressure and the residue was diluted with water and extracted

witr. ether. The ethereal solution was washed successively

with water, sodium bicarbonate solution (5%) and water and

driea over anhyarous sodium sulphate. Removal of the solvent

provided the desired endione (LXXX) recrystallized from

petraleum ether,(1.4 g}, m.p. 123° (reported'*' , m.p.

122-i23°C).

: 56 :

Reaction of 3.6-dioxociolest-4~ene (LXXX; with 2-6minooyridine;

6*'H-Pvriao[2*'.1" ;2',3' |pvrimido|4',5',6';^,5^elcholestan-

S-one (LXXXVI) :

3,6-Dioxochoiest-4-ene'^'* (LXXX) (500 mg; was dissolved

in xylene (10 ml^ and to this was added 2-aminopyridine (100 mg)

anc the mixture was refluxed for six hours. The reaction was

monitored by TLC. Starting compound was not completely changed

into product. After filtration the solvent was evaporated

uncer reduced pressure. The residue was extracted with ether

anc washed several times with water and dried over anhydrous

socium sulphate. Evaporation of the solvent gave an oil

(Ca. 410 mg) which on column chromatography over silica gel

gave two fractions. Elution with a mixture of petroleum ether

anc ether (20:1) afforded LXXXVI(llOmg), m.p. 90°C, which

was similar in all respects (spectral value, n.m.p., ^^C )

vjlzn the compound obtained from the 5-bromo-6-oxo-5a-cholestan-

3^-yl acetate (LXXXVI).

Further elution with the same solvent system (7:1) gave

unreacted compound (LXXX)j(220 mg), m.p. 122° (reported"^^,

m.p. 122-123°C).

Cholest-5-en-36-yl propionate :

A mixture of cholesterol (50 g), pyridine (75 ml) and

propionic anhydride (50 ml) was heated on a water bath for

five hours. The resulting brown solution was poured onto

; 57 :

crushed ice water mixture with stirring. Tne light brown

solid thus obtained was filtered under suction, washed with

water and air dried. The crude product after recrystalliza-

tion from acetone gave the propionate,(45 g), m.p. 100

(reported"^^, m.p. 100°C).

5-Bromo-6g-hvdroxv-5a-cholestan-36-vl propionate :

A solution of cholest-5-en-3^-yl propionate (6.0 g) in

ether (200 mlj was cooled to 5°C. Perchloric acid (0.8 mlj

and N-bromosuccinimide (4.8 g) was added to the ethereal

solution and the mixture was kept at room temperature with

constant stirring for two hours. The ethereal layer was

Washed with water, sodium thiosulphate solution and again with

water and dried over anhydrous sodium sulphate. Evaporation

of the solvent gave an oil, which was crystallized from petro

leum ether to give 5-bromo-6p-hydroxy-5a-cholestan-3p-yl

propionate, (2.5 g), m.p. 138° (reported , .-n.p. 140°C).

5-Bromo-6-oxo-5a-cholestan-3B-vl propionate (LXXXI.) :

5-Bromo-6^-hydroxy-5a-cholestan-3^-yl propionate (5 g)

was suspended in acetone (150 mi; in a three necked round

bottom flask fitted with a stirrer and drorcing funnel. The

suspension was stirred for five minutes anc Jone's reagent

(8 mi; was then added dropwise from a dropping funnel in the

: 58 :

course of 15 minuts.The temperature of the reaction mixture

during oxiaation was maintained between 0--5 C by external

cooling. After the addition, stirring was continued for

additional 15 minuts, cold water (100 ml) was then added.

The solid product thus obtained was filtered under suction,

washed thoroughly with water and dried to give product (LXXXI)

(3.7 g), m.p. 115 . (reported , m.p. 116 C).

Reaction of 5--bromo-6-oxo-5a-cholestan-3S-vl propionate

(LXXXI) with 2-aminopvridine t 6-Oxocholest-4-en-33-vl

propionate (XCV). 5a-pvridori" . 2 " ;1'.2'1imidazor4'.5';6, 7"

cholestan-3B-vl propionate (XCVI) and SS-pyridof 1'* . 2 " ; 1\2']

imidazo["4* .5';6,7]cholestan-3g--vl propionate (XCVIl) :

The ketone (LXXXI) (2 g) was dissolved in xylene (40 ml)

and to this was added 2-aminopyridine (400 mg) and the mixture

was refluxed for six hours. After the usual workup as des

cribed earlier the oily residue Ca 1.78g was chromatographed

over silica gel. Elution with a mixture of petroleum ether

and ether (25:1) gave the compound (XCV) which was recrysta-

llized from methanol (1.0 g), m.p. 132°/ (reported , m.p.

132°C).

^max.^^2^ (C^H^COO), 1680 (C=C-C=0), 1630 (C=C), 1180

(propionate) cm

d 5.93 UH, s, C4-H), 5.23 (IH, m, C3-H, Wl/2=16Hz, ax.).

: 59 :

2.3 (2H, q, CH3-CH2COO), 1.23 (3H, t, CH3CH2COO;, 1.0,

0.91, 0.81 and 0.71 (other methyl protors;.

Analysis Found : C, 78.8; H, 10.6

^30^48^3 ^^qî^^s : C, 78.89; H, 10.59^.

Further elution with a mixture of petroleum ether and

ether (5:1) provided the mixture of isomeric compounds (XC/l)

and (XCVII) which was crystallized from acetone (650 mg),

m.p. 202°C. 0

^ 1735, 1710 (CH^CH„CO), 1600 (0=0), 1572 (C=N) cm"^.

0 8.06 (IH, d, C6"-H), 7.46 (IH, dd, C4"-H), 6.65 (IH,

dd, C 5 " - H ; , 6.42 (IH, d, C3"-H), 5.25 (1/2H, m, C3-H,

tfl/2 = 8Hz, eq.), 4.65 (I/2H, m, C3-Ha, Wl/2 = 18Hz, ax.),

2.97 (LH, m, C7-H), 2.27 (2H, q, CH3CH2CO2), 1.1 (3H, t,

CH3CH2CO2), 0.9, 0.88, 0.85, 0.7 (other methyl protons ).

Analysis Found : C, 79.0; H, 9.7; N, 5.2

^35^52°2'^2 ^^qîês : C, 78.94; H, 9.77; N, 5.26%.

Stiqmast-5-en-33-vl acetate :

A mixture of ^-sitosterol (50 g) pyricine (75 ml) and

freshly distilled acetic anhydride (50 ml) was heated on a

water bath for two hours. A brown solution was obtained

which dfter cooling was poured onto crushed ice water mixture

: 60 :

with stirring. The white precipitate thus Dbteined was

filtered under suction, washed with water and air dried.

The crude acetate was recrystallized from acetone>(45 g),

m.p. 120° (reported"^^, m.p. 120°C).

5-Bromo-6g-hydrQxy-5a-stiqmastan-3g-yl acetate :

Stiginast-5-en-3p-yl acetate (12 g) was dissolved in

ether (200 iml) and cooled to 0°C, to this was added perchloric

acid (1,6 mlj and N-bromosuccinimide (9.6 g). The mixture

was stirred at room temperature for two hours. The reaction

mixture was then extracted with ether. The ethereal layer

was washed with water, sodium thiosulphate solution (5%) and

again with water and dried over anhydrous sodium sulphate.

Evaporation of the solvent gave an oil which was crystallized

from petroleum ether to give bromohydrin^(8 g), m.p. 172 C,

^31^53^3^^' ^max. ^^ ^°"^' ^'^^°' ^'^^'^ ( '3"S"° » < ° (C-3rj .

5-Bromo-6-oxo-5a-stiqmastan-33-yl acetate (LXXXIl) :

To a solution of 5-bromo-6p-hydroxy-ba-stigmastan-3p-yl

acetate (10 g) in acetone (300 mlj, Jone's reagent (15 mi; was

added and the reaction mixture was stirred at 5-10? for two

hours. Excess of chromic acid was destroyea by isopropanol

and saturated solution of sodium acetate. The mixture was

poured into water and the solid, thus obtained was filtered,

air dried and recrystallized from methanol to give the pure

: 61 :

a-bromoketone (LXXXIl), (8.5 g), m.p. 200°' (reported"^^,

m.p. 201°C).

Reaction of 5-bromo-6-oxo-5a-stiqmastan-3g-vl acetate (LXXXIl)

with 2-aminoDvridine ; 6-OxostiQmast-4-en-3g-yl acetate

(XCVIII). 6a-hvdroxv-5ct~pvridori''.2*':1*.2']imidazo[4' ,5' ;

6.7]-4*.5'-dihydrostiQmastan-30-yl acetate (XCIX). 6g-hvdroxv-

Se-oyridon*'.2* *;!'.2*1imidazor4'.5*;6.7]-4«.5*-dihydrostia-

mastan-3p-yl acetate (C), 5a-pyrido[1**.2'*;1*,2*Jimidazo

[4*,5';6.7lstiqmastan-3e-yl acetate (CI) and 5g-pyrido[1* ' . 2 " ;

1'.2*1imidazor4*,5';6.7lstiqmastan~36-yl acetate (CII) :

a-Bromoketone (LXXXIIJ (2 g^ was dissolved in xylene

(40 ml) and to this was added 2-aminopyridine (400 mg) and the

mixture was refluxed for twelve hours. The reaction was moni

tored by TLC. After the usual workup as described earlier tne

oily resiaue (1.78 g) was chromatographed over silica gel.

Elution with a mixture of petroleum ether and ether (20:1)

gave an oil which could not be resolved further due to lack of

quantity.

Further elution with petroleum ether and ether (6:1) gave

the compound (XCVIIl) which was recrystallized from methanol

(350 mg;, m.p.112°. (reported^*^, m.p. 115°C).

^max. 1' ^ CCH3COO), 1680 (C=C-C=0) and 1240 cm"^ (acetate;.

: 62 ;

6 6.03 (IH, d, C4-H), 2.03 (3H, s, CH3COO), 1.1, 0.9,

0.8, 0.75, 0.68 (other methyl protons).

Analysis Found : C, 79.1; H, 10.7

^31^50^3 êqî^^s : C, 79.09; H, 10.71%.

Further elution with the same solvent system (3:1)

afforded the mixture of isomeric compounds (XCIX) and (C)

as an oil 'B' (170 mg). 0

5) 3350 (-0H t° ), 3000 (aromatic), 1730, 1720 (CH'C-0 ),

1600 (C=C), 1570 (C=N), 1240 (acetate) cm""'-.

a 7.5 (2H, m, C6"-H, C4"-H), 6.7 (2H, m, C5"-H, C 3 " - H ) ,

5.5 (1/2H, m, C3-H, Wl/2 = BHz, eq.), 4.96 (1/2H, m,

C3-H, Wl/2 = 19Hz,ax.), 3.4 (IH, s, OH), 2.38 (IH, m,

C7-H), 2.1 and 2.0 (3H, both s, CH3-b-0), 1.0, 0.9,

0.85, 0.76 and 0.66 (other methyl protons).


^36^56^3^2 ^^qî^^s : C, 76.64; H, 9.99; N, 4.96%.

Elution with the same solvent system (2:1) afforded

another uncrystallizable oil *C' (200 mg) which was found to

be a mixture of isomeric compounds (Cl) and (CII).

O i>^^^^ 3000 (aromatic), 1730, 1720 (CH3C-O ), 1600 (€=€),

1570 (C=N), 1240 (acetate) cm"" .

: 63

d 7.6 (2H, m, C6"-H, C 4 " - H ; , 6.7^ (2H, m, C5"-H,

C3"-H), 5.79 (1/2H, m, C3-H, Wl/2 = 7Hz, eq), 4.65

(1/2H, m, C3-H, V.'l/2 = 17Hz^ax), 2.35 (IH, m, C8-H),

2.03, 2.0 (3H, both s, CH^-CTO), 1.0, 0.95, 0.85, 0.5,

0.76 (other methyl protons).


Co^H..O^N^ requires : C, 79.06; H, 9.95; N, 5.12%. Jo D4 2 z

Stiqmast-5-en-33-vl propionate :

A mixture of ^-sitosterol (20 g), pyridine (30 ml) and

propionic anhydride (20 ml) was heated on a water bath for

two hours. The reaction mixture was poured into ice cooled

water, ana the solid thus obtained was filtered under sucxion

washed v.irh water and air dried. Recrystallization of the

crude product from acetone gave stigmast-5-en-3p-yl propionate,

(15 g), r..p. 117° (reported "'", m.p. 117°C).

5-Bromo-6::-hvdroxy-5a-stiqmastan-3g-vl propionate :

Stic.T»ast-5-en-3^-yl propionate (12 g) was dissolves in

ether (200 ml) and to this was added at 0°C, percnloric acid

(1.6 mi; cind N-bromosuccinimide (9.6 g). The mixture was

stirred at room temperature for four hours. The reaction

mixture \^as than extracted with ether. The etnereal layer was

: 64 :

washed with water, sodium thiosulphate 5/o and again with

water and cried over anhydrous sodium sulphate. Evaporaticr.

of the solvent gave an oil which was crystallized from petro

leum ether to give the desired bromohydrin (7.2 g), m.p. 15^ C,

^ 3350 (OH), 1725, l240(C^Hc,C0), 690 (C-Br) cm"^. max. ^ o

5-3romo-6-oxo-5a-stiqmastan-3g-Yl propionate (LXXXIII) :

To a solution of 5-bromo-6-hydroxy-5a-stigmastan-3^-yl

propionate (10 g) in acetone (300 ml), Jone's reagent (15 ml)

was added and the reaction mixture was stirred at 5-10 C for

three hours. Excess of chromic acid was destroyed by iso-

propanol and saturated solution of sodium acetate. The

mixture was poured into water and solid thus obtained was

filtered, air oried and recrystallized from methanol to give

the pure a-oromoketone (LXXXIIl) (8.2 g), m.p. 221 C.

Reaction of 5-bromo-6-oxo-5ct-stiqmastan-3g-yl procionate

(LXXXIII) with 2-aminoovridine : 6-Oxostiqmast-4-en-3B-vl

propionate (CIII). 6a-hvdroxv-5a-pvridor1**.2'';1'.2'linidaro

[4'.5';6.71-^'.5«-dihvdrostiamastan-3B-vl propionate (CIV)

6a-hydroxv-55-cyridoi 1".2":1'.2' jimidazof4' . 5' ; 6. 7 ]-i' . 5'-

dinvdrostiqmastan-36-vl propionate (p/) 5a-pyricoi" 1' ' . 2'' ;

1'.2'Jimidazoi 4'.5* ;6.7 |stiqmastan-3e-vl propionate (CX'l).

: 65 :

5B-PYrldo[l' ' .2' ' :1* ,2' limidazo[4' .5' ;6.7lstiqmastan-:-e-vL

propionate (CVIl) :

Bromoketone (LXXXIII) (2 g) was dissolved in xylene

(40 ml) and to this was added 2-aminopyridine (4CX) mg) and the

reaction mixture was refluxed for twelve hours. The reaction

was monitored by TLC. After the usual work up as described

earlier the oily residue (Ca 1.75 g) was chromatographed

over silica gel. Elution with a mixture of petroleum ether-

ether (15:1) gave the compound (CIII) which was crystallized

from methanol (300 mg), m.p. 135°C. "" 0

-^max. - " ^ (CHQ-C-O ), 1680 (-C=C-C=0), 1630 (C=C) cm"^.

0

0 6.03 (IH, d, C4-H), 2.27 (2H, q, CH3CH2-C~), 1.11 (3H,

t , CH3CH2-C-), 1.0, 0 .9 , 0 .85 , 0 .76, 0.69 (o ther methyl

p r o t o n s ) .

Analysis Found : C, 78,8 ; H, 10.5

^32^52^3 requires : C, 79.28; H, 10.81^.

Further elution with petroleum ether and ether (2:1)

gave a noncrystallizable oil 'D* which was characterized as

inseparable mixture of isomers (CIV) and (CV). 0

^ max, ^^^ (-0H), 3000 (aromatic), 1735 and 1725 (CH2-C-O),

1620 (C=C), 1572 (C=N), 1240 (C-O) cm"^*.

: 66 :

d 7.8 (2H, m, C6"-H, C 4 " - H ) , 6.75 (2H, m, Cb"-H,

C3'«-H), 5.45 (1/2H, m, C3-H, Wl/2 = 8Hz,eq.), 4.95

(1/2H. m, C3-H, Wl/2 = 17Hz,ax.), 3.41 (IH, s, OH), q

2.35 (IH, d, C7-H), 2.27 (2H, q, CH3-CH2-(^-0), 1.2 (3H,

t,CH3-CH2-8-0;, 1.02, 0.91, 0.85, 0.75, 0.65 (other

methyl protons).

Analysis Found : C, 76.5; H, 10.0 ; N, 4.5

C^JH^QO^N^ requires : C, 76.77; H, 10.09; N, 4.84%

Elution with the same solvent system (1:1) gave another

noncrystallizable oil 'E' (230 mg) characterized as mixture

of isomers (CVI) and (CYII).

2) 3000 (aromatic), 1735, 1728 (-CH^-C-0), 1600 (C=C), max. ^

1572 (C=N) cm"-"-.

a 8.1 (2H, m, C6"-H, C 4 " - H ) , 7.5 (2H, m, 05''-H, C 3 " - H ) ,

5.25 (1/2H, m, C3-H, Wl/2 = 7Hz, eq.), 4.7 (1/2H, m,

C3-H, Wl/2 = 17Hz, ax.), 2.9 (IH, m, C8-H), 2.3 (2H, a, O 0

CH3-CH2-C-), 1.12 (3K, t, CH3-CH2-C-), 1.01, 0.95, 0.37,

0.77, 0.o7 (other methyl protons).

Analysis Found : C, 79.3; H, 10.0 ; N, 4.9

37"56°2'* 2 ^qui^es : C, 79.23; H, 10.07; N, 4.99?i.

3Sititxtnm

1. H. Debus, Ann., 107, 199 (1858).

2. E. BdiTJoerger, Ann., 273, 267 (1893).

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4. Kickhofen, Arch. Pharm., 288. 473 (1955).

5. Tschitschibabin, Her., 5^, 1704 (1925).

6. Mosby, Unpublished work, (Cf 3).

7. Tschitschibabin, Ber., 59, 2048 (1926); J. Russ. Phys.

Chem. Soc, 58, 1159 (1926).

8. Schmid and Bangler, Ber., 59, 1360 (1926).

9. T. Takanashi and J. Shibasaki, J. Pharm. Soc. Jaoan,

62, 495 (1949); Chem. Abstr., 44, 4474 (1950).

: 68 :

10. Y.L. Goi'dfrab and M.S. Kondakova, J. Gen. Chem.

(USSR), 10, 1055 (1940); Chem. Abstr., 35, 4020 (l?4l).

11. Reitmann, Ger. Pat. 547, 985, Frdl. 18, 2782 (1933);

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Abstr., Bill, 252 (1932).

12. Reitmann, U.S. Pat. 2,057,978.

13. W.W. Paudler and H.L. Blewitt., J. Org. Chem., 30,

4081 (1965).

14. P.K. Dubey and C.V. Ratnam, Ind. J. Chem., 16B(6). 531

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15. Al-Jallo, N. Hikmat, Al-Biaty and A. Ibtisam, J. Hetero

cyclic Chem., 15(5). 801 (1978).

16. J. Knoll, Z. Meszaros, I. Hermuz, F. Fueloep, G. Bernath,

S. Virag, G. Nagy and P. Szent mi kosi, U.S. 4,291,036

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17. E.S. Hand and vV.W. Paualer, Tetrahedron, 38(1). 49

(1982).

18. G. Roma, A. Ermilis, M. DiBraccio and M. Wazzei Farmaco

Ed. Sci., 37(11), 744 (1982); Chem. Abstr., £8, 53825c

(1983).

69 :

19. J. Binet and P. Manoury, Fr. Demande Fr. 2,510,576;

Chem. Abstr. £9, 139961b (1983).

20. Y. Yokoyama, Bull. Chem. Soc. Japan, 56, 1775 (1983);

Chem. Abstr., 99, 175700z (1983).

21. J.A. Bristor, E\ir. Pat. Appl. EP68378 (1983); Chem.

Abstr., 9£, 38461h (1983).

22. S. Biniecki and W. Modrzejewska, Acta. Pol. Pharm.

41(6). 6U7 (1984); Chem. Abstr., 104, 50843p (1986).

23. B. Alcaide, R.O. Perez-Ossorio, J. Plumet and M.A.

Sierra, Tetrahedron Letters, 26(2). 247 (1985).

24. P.G. Sokov, J. Gen. Chem., O, 1947 (1940).

25. K.C. Joshi, V.N. Pathak and S. Sharma, Ind. J. Chem.,

24B. 124 (1985).

26. A. Monge, M.V. Martinez, E. Canarruzabeitia, B. Lasheras

and E.F. Alvarez, Eur. J. Med. Chem. Chim-Ther. 20(1),

61 (1985); Chem. Abstr., 103, 1,04912k (1985).

27. R. Rydzkawski, D. Blondeau and H. Sliwa, Tetrahedron

Letters, 26(21). 2571 (1985).

28. Fuzisawa Pharmaceutical Co. Ltd. Japan Kokai Tokkyo Koho

Japan, 61 56180 (1986); Chem. Abstr., JOS, 97493k (1986).

: 70 :

29. P. George and J. Allen, Fr. Demande FR 2,581,646 (1985);

Chem. Abstr., 107, 59031s (1987).

30. S. Munavalli, F.L. Hsu and E.J. Poziomek, Chem. Ind.

(London), 7, 243 (1937).

31. F. Fulop, I. Huber, G. Dombi and G. Bernath,

Tetrahedron, 43(6). 1157 (1987).

32. P. George, C. Giron and J, Frossant, Fr. Demande FR.

2,593,818 (1987); Chem. Abstr., 108, 131816s (1988).

33. J.B. Press, U.S. US 4,727,145 (1988); Chem. Abstr.,

108. 221703g (1988).

34. A. Gueffier, J.C. Teulade, C. Francois, H. Viols,

A. Micnel, M. Boucard and J.P. Chapat, Fr. Demande Fr.

2,638,161 (1988); Chem. Abstr., 114, 42788r (1991).

35. P. Catsoulacos and E. Souli, J. Heterocyclic Chem.,

11, 87 (1974).

36. S. Nikolaropoulos and P. Catsoulacos, J. Heterocyclic

Chem., 25(6), 1607 (1988).

37. H.B. Henbest and T.I. Wrigly, J. Chem. Soc, ^596 (1957).

38. R.W. Silverstein, G.C. Bassler and T.C. Morril, Spectro-

metric identification of organic compound, Jonn Wiley

and Sons (1981) .

: 71 :

39. N.S. Bhacca and D.H. Williams, Application of Nm

Spectroscopy in Organic Chemistry, Holden-Day, Inc.,

(1964).

40. H. Reich, F.E. Walker and R.W. Collins, J. Org. Chem.,

i6, 1753 (195i;.

41. C.E. Anagnostopoulos and L.F. Fieser, J. Am. Chem. Soc.

76, 532 (1954).

42. R.M. Dodson and B. Reigel, J. Org. Chem., L3, 424 (194S;.

43. I.M. Heilbron, E.R.H. Jones and F.S. Spring, J. Chem.

Soc, 801 (1937).

44. A.H. Milburn, E.V. Truter and W.P. Woodford, J. Chem.

Soc, 1740 (1956).

45. Ph.D. Thesis of S. Zia Ahmad, AMU, Aligarh (1986).

46. Ph.D. Thesis of I.A. Ansari, AMU, Aligarh (1983).

47. R.H. Baker and E.N. Squire, J. Am. Chem. Soc, 74,

1487 (1948).

48. J.R. Bull, E.R.H. Jones, G.D. Meakins, J. Chem. Soc,

2601 (1965).

: 72

49. C.W. Shopper, R.H. Jenkins and G.H.R. Summers,

J. Chem. Soc, 1657 (1958).

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51. Ph.D. Thesis of S. Masarrat All, A/^, Aligarh (1986)

CJapter-tKhJO

BENZOTHIAZEPINES

Zl^toxttitul

Interest in seven membexed heterocycles wita three

double bonds in the ring has sprung up in the last few years

in connection with studies of aromaticity and of the valuable

therapeutic properties^ " o f some of the compounds of this

group.

Thiazepines are seven membered heterocycles having

nitrogen ano sulphur as the hetero atoms; these may be

1,2-thiazepine (l), l,3-thia2epine (ll), 1,4-thiazepine

(III) and 1,5-thiazepine (IV) depending upon the position

of nitrogen and sulphur in the ring system.

( i ; ( i i ; (IV)

: 74 ;

Benzo-annelated compounds of thiazepines called as

benzothiazepines (I-P/) are claimed to exhibit a wide spectrum

of pharrr.acological activities as txanquilizing, antibacterial,

(7-13) neuroleptic, anticonvulsive, antidepressant etc.

Hence, synthetic chemists have taken interest in the prepara

tion of such derivatives, a brief survey is given below in

chronological order.

The literature reveals that perhaps first benzothiazepine

14 derivative was reported by Mills and coworkers . They

synthesized 2-phenyl-2,3-dihydro-l,5-benzothiazepine-4(5H)-one

(VII) by the reaction of 2-aminothiophenol (VI) and cinnamic

acid (V).

NH. Ph-CH = CH-CCXDH

(v; •a:

(VI)

15

(VII) J ^0

Krapsho et al. obtained 2-phenyl-l,5-benzothiazepin-4

(5H)-one (IX) by the reaction of 2-aminothiophenol with

phenyl propiolic acid (VIII).

Ph-C = C-COOH +

(viii; (VI)

: 75 :

Condensation of 2-aminDthiophenol hydrochloride anc

phenyl-1-propenyl ketone (X) afforded 2,3-dihydro-2-methyl-

4-phenyl-l,5-benzothiazepine hydrochloride hydrate (XI)

which was reduced to 2-methyl-4-phenyI-2,3,4,5-tetrahydro-l,

b-benzothiazepine (XII) by sodium borohydride

0 II

CH3-CH = CH-C-Ph +

(X) (VI)

(XI)

(XII)

1 ,5 -Benzo th i azep ine s may a l s o be p repared by r e f l u x i n c

2 - amino th iopheno l (Vl) and ^ - p i p e r i d i n o p r o p i o p h e n o n e (XII I )

i n xy lene in t h e p r e sence of h y d r o c h l o r i c a c i d . During tne

r e a c t i o n water was c o l l e c t e d , and t h e mix ture was worked ur 17

t o g i v e 2 , 3 - d i h y d r o - 4 - p h e n y l - 6 , 7 - b e n z o - l , b - t h i a z e p i n e (XI\')

i n 355^ y i e l d . CHoCHoCPh I B

( X I I I ) (VI) (XIV)

: 76 :

Beckrnann xearrancement of thioxanthone oxime (X^/) by 18 polyphosphoric acid geive dibenzothiazepin-4-one (XVI) in

38% y i e l d .

H

(xvi;

Reaction of ethyl-3-phenylglycidate (XVIl) with 2-amino-

thiophenol (Vl) gave two products, ethyl-2-hydroxy-3(2-amino-

phenylthio)-3-phenylpropionate (XVIII) and 2-phenyl-3-hydroxy-

2,3-dihydro-l,5-ben2othiazepin-4(5H)-one (XIX)-*" . The

20 compound (XIX) is useful as tranquilizer

Ph-CH-CH-COOCoHps + \ / ^ ^ 0

(xvii; (VI)

NH2^°^2^5

(XVIII) Ph

(XIX)

: 77 :

21 Kalman et al. reported the condensation of 2-amino-

thiophenol (VI) with 2-pipericinomethylcyclohexanone (XX)

by refluxing them in xylene and obtained the benzothiazepine

(XXI}.

SH

Oc„ CXX) (VI) (XXI)

22 Ito et al. reported the synthesis of l-methyl-2-

phenyl-1,2,3,10-tetrahydro-4H-pyra2olo[3,4-C][l,SJbenzo-

thiazepin-3-one (XXV) by the Ullmann reaction of 1-phenyl-

2-methyl-3-(2-aminophenyl)thiomethyl-4-bromo-3-pyrazolin-5-

one (XXIII). XXIII was prepared by the r e a c t i o n of

2-aminothiophenol (Vl) with l-phenyl-2-methyl-3-bromomethyl-

4-bromo-3-pyra2olin-5-one (XXIl). However XXIII under

s i m i l a r condi t ions and DMF as solvent afforded l -pheny l -2 -

methyl -3- (2-benzoth iazoly l ) -3-pyra2ol in-5-one (XXIV)^^.

CH3 L CH_Br , . , - r \ /SH

V' ''' * ^ 5> H-e (XXII) (XXIII)

X, V T ^ l p g

; 78 ;

CH-

Ph-N n v^^v Pyridi

(XXIII) r '-\j (XXV)

11 (XXIV)

The reaction of 2-(N-alkylamino)-thiophenols (XX /I,

XXVII) with methyl-4-methoxyphenyl glycidate (XXVIII) was

carried out to give methyl-2-hydroxy-3-(4-methoxyphenyl)~

3-(2-alkylaminophenylthio)-propionate (XXIX, XXX) which on

hydrolysis followed by the cyclization of the resultant

amino acids afforded N-substituted benzothiazepine, 2-(4-

methoxyphenyl)-3-hydroxy-5-(2-diethylaminoethyl)-2,3-aihyGro-

1,5-benzothiazepin-4 (5H)-one (XXXI) and 2-(4-methoxyphenyl)-

3-hyaroxy-b-methyl-2,3-dihydro-l,5-benzothiazepin-4 (5H)-one

(XXXII) 23

NHR

R

/ \ " V CH^OV V - C - C-COOCHo

(XXVIII)

(XXVI) CH2CH2N(C2Hp^)2

(XXVII) CH,

: 79 :

PCH, CX:H-

OH (i)hydrolysis

(iijcyclization COOCH,

R

(XXXI) CH2CH N(C2H5)2

(XXXII) CH3

(XXIX) CH2CH N(C2H5)2

(XXX) CH3

2-(a-Methyl-o-bromobenzylthio)-aniline (XXXIII) was

heated with potassium carbonate in the presence of copper

powder and pyridine to give dibenzothiazepine (XXXIV),

useful as a tranquilizer 24

(XXXIII) (XXXIV)

Micnael acdition of 2-aminothiophenol to an atropo-

nitrile (XXXV) proceeced exothermall/ to give a p-(2-an-iino-

phenylthio)hydratroponitrile (XXXVl) which on refluxing in

ethanol gives 4-amino-3-phenyl-2,3-dihydro-l,5-ben2othiazepine

(XXXVII). Similarly, 2-aminothiophenol reacted with an

: 80 :

atropic acid (XXXVIII) to afford a ^-(:-amlnophenylthio)

hycratropic acid (XXXIX). Cyclization of XXXIX in dicyclo-

hexyl carPodiimide occurred readily to give 3-phenyl-2,3-

dihydro-l,5-benzothia2epin-4 (5H)-one (XL) 25

: : ^ \ \ II C~CN +

(XXXV)

(xxxviii;

(VI )

SCK2CH . fV %\-^ (XXXVI)

NH.

(XXXVII)

COOH

0(y6 H O

(XL)

: 81 :

The benzothiazepine (XLIl) was prepared by condensation

of 2-aminothicphenol (Vl) with 3-dimethylc-tminomethyl-4-cr-ro.T.a-

p.one (XLI). Derivatives of XLII demonstrated sedative ar.c

muscle relaxant activity

(XLI)

CH3 C«2^<CH

(VI;

SH

(XLII)

Pyrido[2,3-b][l,5]thiazepinone (XLVI) was prepared by

the reaction of 3-aminopyridine-2-thiol (XLIIl) with ^-chloro-

propionic acid (XLIV) in the presence of an alkali metal

hydroxide followed by cyclization of the resulting acid (XLV) 27

m the presence of dicyclohexylcarbodiimide in solution

(XLIII)

+ CI-CH2CH2COOH

(XLIV)

->

N''''' SCHoCHoCOOH ov no*-

(XLV)

(XLVI)

: 82 :

Lf'vai et al. reported the synthesis of 2,3--ihydro-2,

4-diphenyl-l,5-benzothiazepine (XLVIII) by the reaction of

2-aminothiophenol (VI) with chalcone (XLVIl).

(xLvii; (VI) (XLVIII)

4-Methoxy-6-mercapto-5-aminopyrimidine (XLIX) v/ith

^-bromopropionyl chloride gave 4-methoxy-6-mercapto-5(^-bromo-

propionamide)-pyrimidine (L) which on cyclization orovided

pyrimido[4,5-b]-l,5-thiazepin-4-one (Ll)

OCH-

N-'-^^2

il N ^ "SH (XLIX)

BTCH2CH2COCI -5>

OCH H 3 I n

CI ) Br

(L)

f ""3 L/C

(LI)

30

Schmidt reaction of thioflavanone (LII) afforded

2-phenyI-2,3-dihydro-l,5-benzothidzepin-4l5H)-one (VII) and

2-phenyl-2,3-dihydro-l,4-benzothiazepin-5(4H)-one (LIIl).

: 83 :

00"" S Ph

eg. (LII) (VII) (LIII)

Malonic acid (LIV) on condensation with 2-aminothioDhenol

in the presence of dicyclohexylcarbodiimide gave i,5-benzo-

thiazepine-2,4-(3H,5H)-dione (LV) 31

COOH

CH. * OC" ^-COOH

(LIV) (VI)

Treatment of dicarbethoxy monophenyl ethylene (LYI) with

2-aminothiophenol afforded (LVII), which was cyclized in the

presence of base to provide 2-phenyl-3-hydroxyinethyl-2,3-di-

hydro-1,b-benzothiazepin-4C5H)-one (LVIIl)^^.

Ph-CH = C

(LVI)

C00C2H^

C00C2H^

SH / ^ - \>^^^2"5

(LVII)

: 84 :

First one-step photochemical synthesis of 1,5-benzo-

33 thiazepines '•'•as reported by Neckers .;t al. in 1982. They

carried out tne pnotocycloaddition reaction of 2-phenyl-

benzothiazole (LIX) with electron rich alkynes, such as

ethoxyacetylene and 1-ethoxy-l-propyne. Irradiation of LIX

in the presence of ethoxy acetylene gave two products,

3-ethoxy-4-phenyl-l,5-benzothiazepine (LX) ana 3-ethoxy-2-

phenyl quinoline (LXI) in 25% and 13? yield respectively.

h^ Ph+HCs=C-OC2H5-

(LIX)

13 In 1982 Mane et al. reported the synthesis of 2-phenyl-

4-(4'-methyl-2*-phenylaminothiazol-5'-yl)-2,3-dihydro-l, 5-

benzothiazepine (LXIII) by the reaction of 5[3'-phenylacrylo]-

4-methyl-2-phenylaminothiazole (LXII) with 2-a.'ninothiophenol

(Vl) in ethanol in the presence of pipericine, followed by

cyclization witn acetic acid.

7^'^m CTS?

(LXII) {VI)

: 85 :

f \ 34 Benzothiazepine derivative (LXVj was obtained in one

step by the condensation of 2-aminothiophenol (VIJ with

unsaturated ketone (LXIV) in the presence of trifluoroacetic

acid.

(LXIV)

HPh +

(VI) (DCV)

2, 3-Dihydro-2-(4'-hydroxyphenyl)-4-phenyl-l,5-benzothia-

35 zep ine (LXVII) was prepared by r e a c t i n g s u b s t i t u t e d chalcone

( L X V I ) wi th 2 - a m i n o t h i o p h e n o l .

H O - / / y-CH=CH-(':-Ph + • ^

(LXVI) (VI) (LXVII)

N - S u b s t i t u t e c a - a m i n o a c r y l i e acid ( L X V I I I ) was s t i r r e d

i n e t h a n o l wi th 2 -dmino th iopheno l ( V i ; to g ive LXIX which

was r e f l u x e d in xy lene to p rov ide aminobenzoth iazep inones

(LXX)^6.

: 86 :

0 II

CH^=C-NH-C-OCHoPh + 2 I ^

CCCH

(L)C/ I I I ) (VI)

->

(LXIX)

CCOH

2-CH-NH-C

PhCH2-0

0 II

VNH-C-0CH2Ph

(LXX)

3 - n - P r o p y l - 2 , 3 - d i h y d r o - i , 5 - b e n z o t h i a z e p i n - 4 ( 5 H ) - o n e

37 (LXXII) was prepared by the reaction of 2-aminothiophenol

(VI) wi^h 2-hexenoic acid (LXXI) by stirring at room tempe

rature in the presence of acetic anhydride.

CH3CH2CH2CH=CH-C00H + |' I

(LXXI) (VI)

->

CH2CH2CH3

2-Aminothiophenol (VI) when treated with Me2NCH=CH-C^H

(LXXIII) in benzene at 0-5°C gave 2-N,N-dimethylamino-4-

methyl-tH-l,5-benzothiazepine (LXXIV)^®.

(CH3)2N-CH=CH-C=CH +

(L<XIII) (VI)

NMe,

(LXX IV)

: 87 :

A number of 4 -a ry l -2 -ca rboxy-2 ,3 -d ihydro- l ,5 -benzo th ia -

zepines (LXXVI) were prepared by 2-aminothiophenol (Vl) and

a, p!-unsaturated ketoacids (LXXV) 39

COOH /

HC. COOH

(LXXV) (LXXVI)

R = H, 4-CH3, 4-OCH3, 4-Cl, 2,4(CH)2

2-Aminothiophenol (Vl) when heated with p-bromobenzoyl-

acetone (LXXVII) in DMSO or pyridine gave 2,3-dihydro-2-

hydroxy-2'

(LXXVIII)'

hydroxy-2-p-bromophenyl-4-!nethyl-l,5-benzothiazepine >40

Br Br

( v i ; (DCXVIII)

: 38

4-Metnoxy-4'-chlorobenzalace ;ophenone (LXXIX) on

r e a c t i o n v/ith 2-aniinothiophenol O/l) in toluene gave

4- (p-ch lorophenyl ) -2- (p-methoxyphenyl ) -2 ,3-d ihydro- l ,5 -

\4l benzothiazepine (LXXX;

OCH3

(VI)

->

CCH,

(LXXIX) (LXXX)

42

Musnfiq and Iqbal reported the synthesis of 1,5-

benzothiazepine in the cholestane series using different

a,^-unsaturated ketones with 2-aniinothiophenol. They reported

that cho:est-4-en-6-one (LXXXI), its 3^-acetate (LXXXII)

and 3^-propionate (LXXXIIl) derivatives afforded 2',3'-ai-

hydro-5a-cholestano[4a,6-bcj-l',5*-ben2othiazepine (LXXXI/;,

its Sp-yl acetate (LXXXV) and 3p-yl propionate (LXXXVI),

respecti.ely. While cholesta-2,4-dien-6-one (LXXX\'II) gave

2',3',4*,o'-tetrahydro-5a-cholestano[2a,4a-bc]-l',5'-benzc-

thiazepine-6-one (LXXXVIIl)'^^.

: 85 :

(LXXXI)

(DOCXII)

(DCXXIII)

R

H

CAc

OPr

->

(uaxiv) (LXXXV)

(LXXXVI)

R

H

OAc

OPr

->

o - - ^ (LXXXVIi; (LXXXVIII)

43 They also reported the formation of 2*,3'-cihydro-

5a-cnolestano[5,6,7-bc][l',5*Jbenzothiazepine ( XCIl), its

3^-yi acetate (XCIIl) and 3^-yl propionate (XCIV; from

cholest-S-en-y-one (LXXXIX) and its derivatives (XC, XCl).

: 90 :

CgHj y

(VI)

(XCII) H

(XCIII) OAc

(XCIV) OPr

In continuation of their work they prepared spiro

compounds (XCVIl) and (XCVIII) from 3-oxocholest-4-ene

(LXXXIX) H (XC) OAc

(XCI) OPr

(XCV) anc i t s 6p-bromo analogue (XCVI) 44

CsHl?

a" (XCV)

(XCVI)

R

H

Br

(XCVII)

(XCVIII)

R

H

Br

• 01 .

3,6-Dioxocholest-4-ene (XCIX) gave an inseperable

mixture of 6-oxo-ba-cholestan[^a,3-bJDenzothiazine (C)

anc its b^-isomer (Cl). While 3-oxocholesta—^, 6-ciiene

(CII) gave CIII .

(XCIX) (C) ba

(CI) 5P

(CII) (CIII)

Ws^tnUfim

A number of papers dealing with the reaction of 2-amino-

thiophenol with different a,^-unsaturated ketones in order

to prepare various types of l,5-benzothiazepine3 have aopeared

in the recent past. Our lab has been engaged in the prepara-

42—44 tion of steroidal benzothiazepines , and in continuation

few attempts are carried out for the preparation of benzotnia-

zepines in stigmastane series. This part deals with the study

of some easily accessible ketones in the stigmastane series

such as 6-oxostigmast-4-en-3^-yl acetate (CIV), 6-oxostigrr.ast-

4-en-3p-yl propionate (CV), 7-oxostigmast-5-ene (C/I), 7-oxo-

stigmasta-3,5-diene (CVII), 7-oxostigmast-5-en-3^-yl chlorice

(CVIII^, 7-oxostigmast-5-en-3^-yl acetate (CIX), 7-oxostigmast-

5-en-3^-yl propionate (CX), 3,6-dioxostigmast-4-ene (CXI).

The products obtained were characterized on the basis of tneir

spectral and chemical properties.

93 :

^10^21

(CIV)

(cv)

R

OAc

OPr

1C--2:

(cvi;

(CVIII)

(CIX)

(cx;

R

H

CI

QAc

OPr

<;io"2i

(cvii; (CXI)

Reaction of 6-oxostiqma5t-4-en-3g-vl ace ta te (CIV) witn

2-aminotnlQDhenol ; 5a -5 t iqmas tan[4a ,6 -bc1-2 ' •3 ' -d ihvcro-

1 ' , 5 ' -benzo th l azep in -3p -y l ace ta te (CXII) :

45 The ketone (CIV) on treatment with 2-aminotniorhenol

and c a t a l y t i c amount of hydrochloric acid affordec a s ingle

: 94 :

compound,m. p. 18b C, which was analysed for C2yHp p 02NS

(Mt 577). The elemental analysis indicated that the reagent

has been incorporated during the reaction process. Thus on

the basis of precedence six isomeric structures CXII-CXVII

may be proposed for the compound, m.p. 185 C

^10^21

AcO

(CXIIj 4a- (CXIV) 4a- (CXVl) 4a-

(CXIII) 4^- (CXV) 4p- (CXVII) 4^-

The i.r, spectrum of the compound showed absorption

,i-o-;. bands at 1740s, 1245s (CH3-C-O-;, 1580 (C=li), 740s iC-S),

3065, 1645 cm"-"- (aromatic )^^. Structure CXVI and CXVII

were aiscarded since N-H region was devoid of any band. The

n.m.r. spectrum of compound, m.p, 185° showed two multiplets

centered at d 7.1 and 6.7 integrating for two protons each

ascribable to four aromatic protons. Another .Tultiplet at

6 5.05 integrating for one proton was assigned to C3-aH.

: 95 :

Half band width (17Hz) of this proton incicatea tnat tne

proton at C-3 is axial, which in turn implies A/3 ring junc

tion as trans. Tnus structures CXIV and CXV with cis ring

junction could also be discarded.

The choice narrowed down to the two isomeric structures

CXII and CXIII witn the difference in the stereocnemistry of

C4 having sulfur as a- or ^-oriented respectively. The disti

nction could be made on the basis of the nature of the C4-H

signal in the n.m.r. spectrum. The multiplet at d 2.8 could

be assigned to the C4-proton. The half band width lOHz coulc

be rationalized better if we consider it to be axial, ^-oriented

rendering sulfur as a-oriented. Therefore, the structure

CXII is preferred over the possible isomeric structure CXIII

for the compound, m.p. 185°C.

A singlet at v3 2.0 integrating for three protons was

assigned to acetate methyl. Other signalswere observed at

d 1.0, 0.9, 0.8, 0.75, 0.7 (other methyl groups)"^^. Thus, on

tne basis of above discussions the compouna, m.p. 185°C, has

been characterizec as 5a-stigmastan-[4a,6-bc]-2',3'-dihydro-

1',5'-benzothiazepin-3^-yl acetate (CXH;.

: 96 :

Reaction of c>-oxostlamast-4-en--3g-vl propionate (CV) with

2-aminothlophenoI : 5a-Stiamastan-[4a. 6-bc1~2* .3*-cllhydro-

l'.5'-benzothia2epin-33~vl propionate (CXVIIl) :

The ketone (CV) on treatment with 2-aminothiophenol and

a catalytic amount of hydrochloric acid afforded a single

compound, m.p. l9o°c»analysed for ^28^b7^'^^^ ^^^ 591). Mole

cular weight ana analytical data hold good for six possible

structures CXVIII-CXXIII given below.

PrQ

^10^21

(CXVIIl) 4a-

(cxix; 4 -

S N \ /

O (CXX; 4 a -

(CXXI) 4/3-

S N - H \ / o

(CXXIIj 4 a -

(CXXIII) 4 p -

The i.r. spectrum of the compound showed absorption

bands at 1735 (propionate), 1580 (C=N), 740 (C-S), 3065, -1 l6bO cm (aromatic).

: 97

The n.m.r. spectrum of the compound showed two multi-

plets at d 7.1 and 6.8, for t.vo protons each assigned to

aromatic protons. Another noltiplet at d 4.8 integrating

for a single proton assigned to C3a-H, half band width (l^Hz)

of this proton indicated the proton at C-3 as axial wnich in

turn implies A/B ring junction as trans. A multiplet at d 3.1

Wl/2 = llHz integrating for one proton could be assigned to

C4-pH, rendering the sulfur as a-oriented. A quartet at Q II

d 2.32 integrating for two protons was assigned to (CH^-CHj"'^"^

and a triplet at d 1.17 integrating for three protons assigned O II

to (CH^CH^-C-). Other signals were obtained at d 1.02, 0.98,

0.85, 0.78, 0.69 (methyl protons). Thus on the basis of above

spectral evidences and in analogy with the previously dis

cussed product (CXII) the compound, m.p. 196 , has been

characterized as 5a-stigmastan-[4a,6-bc]-2',3'-dihydro-l', 5'-

benzothiazepin-3^-yl propionate (CXVIII).

Reaction of 7-oxostiqmast-5-ene (CVI) with 2-aminothioohenol :

5a-Stiqmdstan|"5.7-bc 1-2*. 3'-cihvdro-1* . 5*-benzothiazepjne

(CXXIvf :

The ketone (CVI) on treatment with 2-aminothiophenol and

catalytic amount of hydrochloric acid afforded a single

compouna ds a non crystallizaole oil 'A', analysed for

^35^53^^- Molecular weight (V.t 519) and analytical data of

This co.npound may also be called as 5,7-epithioL 1,2]benzeno-nitrilo-5a-stigmdstane. M. .'.(ushfiq and G. Mudgal, J. Chem. Res.(S) (In press'.

: 93 :

the compound r.old good for two possible strjctires CXXIV and

CXXV both wixn ring junction trans on the basis of analogy

with the compounds as reported earlier

^10^21

N-H


banas at 3000 and 1620 (aromatic), 1582 (C=N), 730 cm" (C-S).

Tnese values favour the structure CXXIV, as the possible

isomer (CXX"/) can be rejected due to the absence of band at

the region above 3300 for N-H group. The n.m.r. soectrum of

tne oil 'A* snc fed two multiplets at b 7.25 and 7.06 each

integrating for two protons, assigned to aromatic protons.

Ano-her multiplet at d 2.6, integrating for three protons was

ascribable to C:.~H^ and C8-H. Signals for methyl groups were

obtained at 1.C2, 0.98, 0.85, 0.76, 0.68. On the basis of

above data the cil 'A* may be tentatively characterized as

5a-stigmastan-:!,,7-bcJ-2',3«-dihydro-l',5'-benzothiazepine

(CXXIV;.

: 99 :

Reaction of 7-oxostiqmasta-3,5-diene (CVII) with 2-arr.inothic-

phenol ; 7-Qxo-5a-stiqmastar.[3a, 5-bc1-2* • 3* , 4', 5'-tetrah 'dro-

1*. 5*-benzothiazeDine (CXXVIj and 7-(2-imir.othloDhenol)-jg-

5tiqmastan[3a,5-bc J-2',3*.4'.5*-tetrahvdro-1*,5*-benzothiaze-

pine (CXXVII) :

The dienone (CVII) was treated with 2-eminothiophenol

and catalytic amount of hydrochloric acid. Usual work up of

the reaction mixture in usual manner followed by column chro

matography over silica gel afforded two tractions,a noncry-

stallizable oil 'B' and a solid compound, m.p. 169°C-

^10^21

(O/II)

(XXVII)

Cnaracterizatioi oi oil 'B' as 7-oxo-5a-stianastan-L3a,5-cc]-

2' .3'.4'.5'-tetrahvdro-l'.5'-benzothiazeoine (CXr/l) ;

Tne oil 'B* was analysed for C3P^H^30NS (Mt 519). The

i.r. spectrum showed an absorption band at 1710 cm"-'- incicating

the presence of carbonyl group. Other absorption bands were

observed at 3320 (N-H), 3000, 1600 (aromatic), 1650 (C=C),

750 cm"-'- (C-S).

Thus on the basis of molecular composition and i.r.

values obtained, four possible structures CXXVI, CXXVIII-

CXXX may easily be proposed for the oil 'B*.

10^21

(, CXXVI) 5a-

(cxxviii;^^. (CXXIX) 5a-

(CXXX) 5^-

101 :

The n. n.r. spectrum of the oil 'B' shov,9ci a broad

multiplet centered at d 6.3 (4H-aromatic}, 5.25 (IH, NH),

3.8 m(lH, C3-H, Wl/2 = 5Hz), 2.27 m(C6-H2 and CS-H} along

with methyl proton signals at d 1.05, 0.95, 0.8, 0.75 and

0.7. The signal at d 2.27 with Wl/2 = 5Hz suggested that

03 proton is equatorial in nature which is oossiole only

in structures CXXVI and CXXX thus discarding the structure

(CXXVIII) and (CXXIX). This was further supported by the

drieding model which also suggested that sulfur at C-3 anc

nitrogen at C-5 can have the same orientations. A clear

distinction between the two structures CXXVI and CXXX both

having C-3 equatorial proton could not be ascertained, but

on the basis of the fact that the drieding model of the

structure CXXVI with A/B ring junction as trans seems to have

lesser strain and this being of more common occurrence, the

compound can best be characterized as 7-oxo-5a-stigmastan-

[3a,5-bc]-2' ,3' ,4',5'-tetrahydro-1*,5*-benzothiazecine (CXXVI)

Characterization of the compound, m.p. 169 as 7-(2-iniino-

thioDhenol)-5a-stiqmastan-[3a.5-bc1-2 *,3*,4*.5*-tetrahvdro-

l* . 5'-benzothiazeoine (CXXVII) :

The compound with m.p. 169° analysed for C^,H^,N-^S^ ' 41 58 2 2

(M. 6 4 2 ) . The i . r . spectrum ot t he compouna showea bands at

3350 (N-H), 3000, 1600 ( a r o m a t i c ) , 1580 (C=\'), 740 cm"^ (C-S) .

: 1C2 :

Tne molecular composition and absence of a band for carbonyl

frequency suggested that two moles of the reagent have been

incorporated. It is therefore considered that the unsaturated

centre and carbonyl group both are involved in the overall

reaction most likely in the same sequence. Thus on the basis

of above discussion we may suggest two structures CXXVII anc

CXXXI for the compound, m.p. 169 C.

10^21

CCXXVII) (CXXXI)

The distinction between the two compounds was made on

the basis of n.m.r. spectrum which showed multiplet at d 3.5

with Wl/2 = 5Hz ascribable to C3-H. Half band width of this

proton suggested this proton as equatorial and ^-oriented

rendering the sulfur moiety as a-oriented. Alternate struc

ture CXXXI was discarded since it has sulfur as (S-orientec.

This is further supported by the drieding model of the

compounc whicn suggest that sulfur at C3 and nitrogen at C5

: 103

can have the same orientations. A complex multiplet at

d 7.46 - 6.32 integrating for eight protons was assignea to

aromatic protons. Two multiplets at d 3.75 and 4.^ eacn

integrating for single proton were assigned to hyarogen

attached to sulfur and nitrogen respectively. A multiolet

at d 2.6 integrating for three protons assigned to 2 protons

at C-6 and one proton at C-8, A multiplet centerec at - 1.72

for four protons could be ascribed to C-2 and C-4 protons.

Signals for angular and side chain methyl protons were

obtained at d 1.03, 0.95, 0.85, 0.80, 0.72. Thus the comocund

m.p. 169 Cjhas been characterized as 7-(2-iminothiophenol)-

5a-stigmastan-[3a,5-bcJ-2',3*,4*,5'-tetrahydro-l',5*-benzo-

thiazepine (CXXVII).

Reaction of 7-oxostiqmast-5-en-33-vl chloride (CVIIIJ with

2-aminothiophenol ; 5a-Stiqmast-3-en-[5.7-bc]-2'^3'-dinvarc-

1* .S'-benzothiazepine (CXXXIl) and 5a-stiamastan[5.7-bc^-2*,

3*-dihvaro-l«.5'-benzothiazepin-3g-vl chloride CCXXXIII) :

The ketone (CVIII) was treated with 2-aminothioDhenol

and catalytic amount of hydrochloric acid. Usual work uo o:

the reaction mixture and subsequent column chromatograpny

over silica gel afforded two fractions as noncrystallizaole

oils 'D' and •£' with a small amount of starting ketone

(CVIII).

IC^

^10^21

(cviii; (CXXXII) (cxxxiii;

Characterization of oil 'D' as 5a-stiamast-3-en-[ 5. 7-bc"'-2'.

3'-dihvdro-l'.S'-benzothiazepine (CXXXII) :

The oil 'D* did not show the presence of chlorine by

Beilstein test and elemental analysis correspondea to the

molecular composition C cHp iNS CM. 517). This suggested

that dehydrochlorination also took place during the course

of reaction. On the basis of the composition two possible

structures CXXXII and CXXXIV may be suggested for the compound

obtainea as oil 'D'.

?io" 21

N-H

(CXXXII)

: ICb :

The i.;-. spectrum of the compouna shc.ea aosorotion

bands at 30)0 (aromatic), 1620 (,C=C), 1580 (C=N), 755 cm"

(C-S). The absence of the band for N'-H vibrations discarded

the structure (CXXXIV). The n.m.r. soectrurn of the comoound

showed a multiplet at d 7.2 integrating for four protons

ascribable to aromatic protons. Two multiolets at d 6.6 and

6.3 each integrating for only one proton assigned to t.vo

vinylic protons at C-4 and C-3 respectively in the structure

CXXXII. Another multiplet at d 2.4 integrating for three

hydrogens was ascribable to Cd-H^ and C8-H. The facts that

two vinylic protons were present and the signal at d 2.4 for

three protons ascribable to C6-H2 and C8-H, further supoorted

the structure CXXXII. The other methyl proton singlets were

observed at d 1.0, 0.95, 0.86, 0.8, and 0.7. Therefore oil

'D* can be tentatively characterized as 5a-stigmast-3-en-

[5,7-bc]-2',3'-dihyaro-l',5'-benzothiazepine (CXXXII).

Characterization of oil *E* as Sa-stigmastan-rs.7-bc1-2* .S'-

cihvdro-l*. 5'-benzothiazepin-3B-vl cnloride (CXXXIII) :

The oil •£• was analysed for C^^H^^NSCl (positive

Beilstein test) .

The i.r. spectrum of the compound showea absorption

bands at 3000 and 1610 (aromatic), 1583 (C=N),' 755 (C-S) and

748 cm"^ (C-Cl).

: 106 :

The n.in.r. spectrum of the compound showed a multip let

at d 7.15 integrating for four hydrogens, which was assigned

to aromatic protons. Another multiplet at d 3.7 (Wl/2 = 14Hz)

was assigned to C3-aH. Half band width of this proton was

a clear incication that the proton is axial and a-orientec

rendering the A/B ring junction as trans. Multiplet at d 2,4

integrating for three protons was ascribed to C6-H2 and CS-H.

Methyl proton signals were obtained at 1.08, 0.85, 0.75, C.7

and 0.6. Tnese spectral values supported the structure

CXXXIII, and the compound oil 'E' can be tentatively charac

terized as 5a-stigmastan[5,7-bc]-2',3*-dihydro-l',5'-benzo-

thiozepin-3^-yl chloride (CXXXIII).

Reaction of 7-oxostiqma5t-5-en-30-yl acetate (CIX) with

2-aminothioohenol ; 5a-Stiqmastan-[5.7-bc1-2*.3'-dihydro-

1'.5'-benzothiazeDin-3e-vl acetate (CXXXV) :

The ketone (CIX^ on treatment with 2-aminothiophenol and

catalytic amount of hyorochloric acid afforded single

compound as noncrystallizable oil 'F', which was analysed for

'"37 55* 2' • " the basis of molecular composition four

possible structures may be suggested for the compound, labelled

as oil 'F'.

: 107 :

910 2.

(CXXXV) ba-

(cxxxvi; 5 -

N-H

(CXXXVII) 5a-

(CXXXVIII) 5p-

The i.r. spectrum of the oil 'F' showed absorption bancs

at 30OO (aromatic), 1720 (CH3-C-O), 1620 (C=C), 1580 (C=N),

1240 (acetate), 720 cm"" (C-S).

The n.m.r. spectrum of the compounc showed two multi-

plets at d 7.15 and 6.56 ascribable to the four aromatic

protons. Another multiplet at d 4.5 (Wl/2 = 17Hz) was assigned

to C3-aH and A/B ring junction as trans. A multiplet at

d 2.4 integrating for three protons was ascribec to C6-I-U and

C8-H. A singlet at d 2.0 integrating for three protons

assigned to protons of acetate moiety. Other methyl protons

signals were obtained at d 1.1, 1.0, 0.92, 0.85, 0.76. These

spectral values supported the formulation ot the compound^a non

crystellizdbleoil 'F* as 5a-stigmdstan[5,7-bcJ-2',3'-dihydro-

l',5'-benzothiazepin-3^-yl acetate (CXXXV).

: ICc

R e a c t i o n of 7 - o x o s t i q m a 5 t ~ 5 - e n - 3 3 - v l p r u p i o n a t e (CX) with

2 - a m i n o t h i c p h e n o l ; 5 a - S t i q m a s t a n - | 5 , 7 - b c l - 2 * t 3 * - d i h y d r o -

1 ' , 5 ' - b e n z o t h i a z e D i n - 3 g - v l p r o p i o n a t e (CXXXIX) :

The ke tone (,CX)on t r e a t m e n t w i th 2-arr . inothiophenol and

c a t a l y t i c amount of h y d r o c h l o r i c ac id a f fo rded s i n g l e comoounG

as n o n c r y s t a l l i z a b l e o i l *G' which was ana lysed fo r C^QHP^-,02NS,

Pr crV^A-^^ -^ ProXJ^

(CX) (CXXXIX)

I.r. spectrum of the compound showed absorption bands

at 3060 (aromatic), 1735 CC2H^-5-0), lo20 (C=C), 1580 (C-N),

7oO cm (C-S). N.m.r. spectrum of the oil 'G' showed a

multiplet at d 7.3 - 6.63 ascribed to fojr aromatic protons.

A multiplet at d 4.2 (Wl/2 = I6H2) ascribed to C3-aH, render

ing the A/B ring junction as trans. Another multiplet at

o 2.61 integrating for three protons assigned to C6-H and

C8-H. A quartet at 0 2.33 integrating for two protons and a

triplet like signal at^l.18 integrating ror three protons

accounted for the five protons of propionate .oiety. Other

: 109 :

methyl proton signals were obtained at 1.06, 0.95, 0.89,

0.75 and 0.68. On the basis of spectral data and analogy wi

the other discussed similar compouncs the oil 'G' may be

tentatively characterized as 5a-stigmastan[5,7-bc]-2',3*-

dihydro-1',5'-benzothiazepin-3p-yl propionate (CXXXIX).

Reaction of 3,6-dioxostiqmast-4-ene (CXI) with 2-aminothio-'

phenol : 3-Oxo-5a-stiQmastan[4a, 6-bcl-2*.3*-dihvdro-l*. 5*-

benzothiazepine (CXL) :

The dione (CXI) was treated with 2-aminothiophenol in

presence of catalytic amount of hydrochloric acid. The

reaction mixture after usual work up afforded an oil 'H*

which could not be further analysed due to lack of quantity

Another noncrystallizable fragment oil '!• was analysed for

C CjHpj ONS. Molecular composition and analytical data hold

good for two possible isomers (CXL) and (CXLI).

10^21

(CXL; (CXLI)

: 110 :

The i.r. spectru-7i of the compound showed tne bands at

3000 and 1620 (aromatic), 1705 (carbonyl group), 1 52 (C=Ny

ana 75b cm (C-S). The i.r. alone was not sufficient to

make a distinction between tne two possiole isomeric structure

CXL and CXLI.

The n.m.r. spectrum of the compounc showed a multiplet

centered at d 6.4 for the four aromatic protons. A distorted

Goublet centered at d 5.6, integrating for one proton could

be assigned to C4-H. A multiplet like signal at d 3.0 for a

single proton assigned to C5-H and another multiplet centered

at d 2.1 for four protons ascribable to C2-H^ and C7-H2,

supported the structure CXL over CXLI. The other methyl

signals were observed at d 1.1, 1.0, 0.95, 0.8 and 0.7.

These analytical and spectral data suggested the formulation

of the compound oil 'I' as 3-oxo--5a-stigmastan-i5,7-bc]-2',

3'-dihyaro-l',S'-benzothiazepine (CXL).

Experimental

6-0xostiqmast-4-en-3g-yl acetate (CIV) :

A solution of 5-bromo-6-oxo-5a-stigmastan-3^-yl acetate

(5 g) in pyridine (50 ml) was heated under reflux for eight

hours under anhydrous conditions. The reaction mixture was

poured into ice cooled water, acidified with dilute hydro

chloric acid and extracted with ether. The ethereal solution

was washed successively with water, sodium bicarbonate solution

(5%) and again with water and dried over anhydrous sodium

sulphate. Removal of the solvent provided an oil which was

crystallized from methanol to give the ketone (CIV) (4.5 g),

m.p. 115 (reported , m.p. 115°C).

: 112

Reaction of 6-oxostiqmas1-4-5n-3B-vl acetate (CIJ) with

2-aminothioohenol ; 5a-Stiqmastanr4a.6-bc]-2'. 3'-Gihvdro-

1* .5*-benzot:hiazepin-3B-vl acetate (CXIl) :

A mixture of the ketone (CIV) (1 g) and 2-aniinothio-

phenol (0.5 g) in absolute methanol (25 ml) having two drops

of cone, hydrochloric acid, was refluxed under anhydrous

conditions for two hours. The reaction progress was monitcred

by TLC. Tne reaction mixture on cooling gave a solid whicn

was filtered, dried and recrystallized from metnanol to give

(CXIl) (0.78 g), m.p. 185°C.

)) 3065 (aromatic), 1740 (CH^COO), 1645 (C=C), 1580(C=N),

1245 (acetate), 740 (C-S) cm""'-.

d 7.1 (2H, m, aromatic, C9«-H, C6'-H), 6.7 (2H, m, aroma'-ic

C8'-H, C7»-H), 5.05 (IH, m, C3-Ha, Wl/2 = 17Hz), 2.8 (IH,

m, C4-H, Wl/2 = lOHz), 2.0 (3H, s, CH3COO), 1.0, 0.9,

0.8, C.75, 0.7 (other methyl protons).

Analysis found i C, 76.6; H, 9.5; N, 2.4

^37'^55°2^ requires : C, 76.89; H, 9.59; N, 2.42%.

6-Qxostiqmast-4-en-3g-vl propionate (CV) :

A solution of 5-bromo-6-oxo-5a-stigmastan-3p-yl propio

nate (2.5 g) in pyridine (25 ml) was heated under reflux for

eight hours under anhydrous conditions. The reaction mixture

: 113 :

was poured into ice cooled water, acidified with dilute

hydrochloric acid and extracted with ether. The ethereal

solution was washed successively with water and dried over

anhydrous soaium sulphate. Removal of the solvent provided

an oil which was crystallized from methanol to give the

ketone (CV) (2.1 g) m.p. 135°C.

7) 1735 (propionate}, 1690, 1620 (-C=C-C=0) cm"^. nictx •

d 4.8b (IH, m, C3-H, ax, Wl/2 = 14Hz), 4.02 (IH, m, C4-H), 0 0

2.32 (2H, q, CH3-CH2-C-O), 1.17 (3H, t, CH3CH2-i'-0),

1.02, 0.98, 0.85, 0.78, 0.69 (other methyl protons).

Analysis found : C, 79.2; H, 10.8

^32^52^3 ^ q'Ji s • C, 79.28; H, 10.81%.

Reaction of 6-oxostiqmast-4-en-3g-yl propionate (CV) with

2-aminothiophenol ; 5a-Stiqmastan-| 4a. 6-bc]-2*. 3'-dihydro-

1*,5*-benzothia2eDin-3e-vl propionate (CXVIIIJ :

A mixture of the ketone (CV; (1 g) and 2-aminothiophenol

(0.5 g) in absolute metnanol (25 ml) having two droos of cone,

hydrochloric acid was refluxed under anhydrous conditions for

two hours. The reaction progress was monitored by TLC. The

reaction mixture on cooling gave a solid which was filtered,

dried and recrystallizea from methanol to give (CXVIIl) (O.^ g)

m.p. 196°C.

: 114 :

3065 (aromatic), 1735 (propionate), 165C [2=0, 1580 "max.

(C=N), 740 (C-S) cm"^.

5 7 . 1 (2H, m, a r o m a t i c , C9 ' -H, C 6 ' - H ) , 6 .8 (2H, m, a r o

m a t i c , CB'-H, C 7 ' - H ) , 4 . 8 ( IH, m, C3-H, ax, Wl/2 = 14Hz),

3.1 (IH, m, C4-H, ax, Wl/2 = llHz), 2.32 (IH, q, O 0

CH3CH2-B-), 1.17 (3H, t, CH3CH2-C-), 1.02, 0.98, 0.85,

0.78, 0.69 (other methyl protons).

Analysis found ; C, 77.1; H, 9.6; K, 2.3

^38^57^2^ requires : C, 77.10; H, 9.71; X, 2.37%.

Stiamast-5-en-3g-vl chloride :

Freshly purified thionyl chloride (20 ml) was added

gradually to ^-sitosterol (25 g) at room temperature. A

vigorous reaction ensued with the evolution of caseous

products. When the reaction slackened, the mixture was

gently heated at a temperature of 50-60°, on a water bath

for one hour and then poured into water with stirring. The

yellow solia thus obtained was filtered under suction and

I'.'ashed several times with ice cooled water and air dried,

fiecrystdllization from acetone gave stigriast-5-6-.-3j3-yl

chloride, (22 g; m.p. 82° (reported^^ , n-..p. 82':).

: 115 :

Stiqmast-S-ene :

Stigmast-5-en-3p-yl chloride (10 g) was dissolved in

warm amyl alcohol (230 ml) and sodium metal (20 g) was added

to the solution with continuous stirring over a period of

eight hours. The reaction mixture was warmed occassionally,

when all the sodium metal was dissolved, the reaction mixture

was poured into water, acidified with hydrochloric acid and

then allowed to stand overnight. A white crystalline solid

thus obtained was filtered under suction and washed thoroughly

with water and air dried. The crude material was recrysta-

llized from acetone to provide stigmast-5-ene (8.2 g), m.p. 75

(reported , m.p. .75 C).

7-0xostiqmast-5-ene (C/l) :

A solution of t-butyl chromate [from t-butyl alcohol

(60 mlj, chromium trioxide (20 g), acetic acid (84 ml) and

acetic anhydride (10 ml)] was added at 0 C to a solution of

stigmast-5-ene (8 g) in carbontetrachloride (150 ml), acetic

acid (80 ml) and acetic anhydride (10 ml). The contents were

refluxed for three hours and then it was diluted with water.

The organic layer was washed successively with water, sodium

bicarbonate solution (5^) and again with water and dried over

.anhydrous sodium sulphate. Evaporation of the solvent under

: 116 ;

reciuced pressure furnished an o i l which was c r y s t a l l i z e d

from methanol, to give 7-oxostigmast-5-ene ( 0 / I j , ( 3 . 6 c)

71.p. 128° ( repor ted^^, m.p. 128°C). m

Reaction of 7-oxostiqmast-5-ene (CVI) with 2-aminothiocnenol :

5a-Stiqmastan-[5.7-50 1-2*.3*-dihvdro-l'.5'-benzothiazecine

(CXXIV) :

A mixture of ketone (CVI) (l g) and 2-aminothiopnenol

(0.5 g) in absolute methanol (25 ml) having two drops of cone,


two hours. Removal of the solvent under reduced pressure

gave an oil, which was chromatographed over silica gel.

Elation with petroleum ether : ether (15:1) afforded an oil 'A'

(CXXIV) (450 mg), which failed to crystallize.

2) 3000 (aromatic), 1620 (C=C), 1582 (C=N), 730 cm"^(C-S).

d 7.25 (2K, m, aromatic, C9'-H, C6'-H), 7.06 (2H, m,

aromatic, C8*-H, C7«-H), 2.6 (3H, m, C6-H and C8-H),

1.02, 0.98, 0.85, 0.76, 0.68 (other methyl protons;.

Analysis found : C, 80.1; H, 10.2; N, 2.7

^as^bs'^^ requires : C, 80.06; H, 10.28; N, 2.69= .

7-0xostiqmast-5-en-3S-vl acetate (CIX) :

To a solution of stigmast-5~en-3^-yl acetate (8 g) in

: 117 :

carbontetrachloride ( 1 ^ ml}, acetic acid (30 ml) and acetic

anhydride (lO ml) was added at 0 C a solution of t-butyl

chromate [from t-butyl alcohol (60 ml) chromium trioxide

(20 g), acetic acid (84 ml) and acetic anhydride (10 ml)].

The mixture was heated under reflux for four hours and the

reaction mixture was diluted with cola water. The organic

layer was washed with water, sodium bicarbonate solution (5' }

and again with water and dried over anhydrous sodium sulohate.

Evaporation of solvent under reduced pressure gave an oil

which was crystallized from methanol to give ketone (CIX)

(3.5 g), m.p. 170° (reported"^^, m.p. 170°C).

7~0xostiamasta-3.5-diene (CVII) :

To a solution of 7-oxostigmast-5-en-3p-yl acetate (5 g)

in ethanol (ICO ml) was added hydrochloric acid (5 ml; 12 X)

and the reaction mixture was heated under reflux for two

hours. Then it was allowed to cool at room temperature, the

solid thus oDtained Was filtered and crystallized from ethanol

to give the dienone (CVIl) (3.5 g), m.p. 104-105° (reportec ,

m.p. 105 ).

Reaction of 7-oxostiqmasta-3. 5-dlene (C /Il) with 2-3minothio-

phenol : 7-C.xo-5a-stiqmastan[3a. 5-bcl-2 ' , 3' .4' . 5'-tetrahvdr.--

l',5'-bpnzothiazeoine (CXXVI) and 7-(2-ininothioDhenol)-5a-

: li;

stiqr.astanr3a.5-bcl-2*.3'.4'.5*-tetrahvcro-l' , 5'-benzothia-

zeoine (CXXVIl) :

A mixture of dienone (CVIl) (1.5 g) and 2-aminothiophercl

(0.75 g) in absolute methanol (35 ml) having two drops of ccr.c.


two hours. The reaction was monitored by TLC. Removal of tne

solvent under reduced pressure gave an oil (Ca. 1.4 g) which

was chromatographed over silica gel (30 g). Elution with

petroleum ether - ether (15:1) afforded the compound (CXXVl)

as a non crystallizable oil 'B* (300 mg).

^^ ^ 3320 (N-H), 3000 (aromatic), 1710 (C=0), 1650 (C=C),

1600 (aromatic), 750 cm"" (C-S).

a 6.3 (4H, m, aromatic), 5.25 (IH, m, NH), 3.8 (IH, m,

C3-K, Wl/2 = 5Hz), 2.27 (3H, m, C6-H2, C8-H), 1.05,

0.95, 0.8, 0.75, 0.7 (other methyl protons).


^35^53^"^ requires : C, 76.17; H, 9.68; N, 2.54? .

Further elution with petroleum ether - ether (2:1)

provided (CXXVII) (400 mg) m.p. 169^.

^max. ^^^^ (N-H;, 3C00, 1600 taromatic), 1580 (C=N),

740 cm"- iC-S).

: 119 :

7.46-6.32 (3H, m, aromatic), 4.4 (IH, m, NH), 3.75 (IH,

m, SH), 3.5 (IH, m, C3-H, Wl/2 = 5Hz), 2.6 (3H, m, C6-H2,

C8-H), 1.72 (4H, m, C2-H2, C4-H2), 1.03, 0.95, 0.85,

0.80, 0.72 (other methyl protons).


C^jH^Q^^S^ requires : C, 76.58; H, 9.09; N, A.26%.

7-QxostiQmast-5-en-3B-vl chloride (CVIII) :

A solution of t-butyl chromate [from t-butyl alcohol

(60 ml), chromium trioxide (20 g), acetic acid (84 ml) and

acetic anhydride (10 ml)], was added at 0 C to a solution of

stigmast-5-en-3^-y1 chloride (8 g) in carbontetrachloride

(150 ml), acetic acid (80 ml) and acetic anhydride (10 ml).

The contents were refluxed for three hours ana then it was

Diluted with water. The organic layer was washed successively

with water, sodium bicarbonate solution (5%) ana again with

Water and dried over anhydrous sodium sulphate. Evaporation

of the solvent under reduced pressure furnished an oil which

was crystallized from methanol to give tne ketone (CVIII)

(4.5g) m.p.l45° (reported^^, m.p. 145*2;).

Reaction of 7-oxostiamast-b-en-36-vl chloride (CVIIl) with

.2-aminothioohenol ; Sa-Stinm s t-S-enfS. 7-bc 1-2 ' . 3 '-djhvdro-

: 120 :

1*.5'-benzothiozepine (CXXXII) and 5a-sti:m£?tan-r5.7-bc]-

2'.3'-dihvdro-l'.5*-benzothiazepiii-3g-yl rhlcride (CXXXIII) ;

A mixture of ketone (CVIII) (2 g) ar.d 2-aminothiophenol

(1 g) in absolute methanol (40 ml) having fojr drops of cone,

hydrochloric acid was refluxed under annycxojs conditions for

four hours. The reaction progress was nor.itored by TLC.

The starting ketone was not completely changed into product.

Removal of the solvent under reduced pressure gave an oil

(Ca. 1.8 g) which was chromatographed over silica gel (40 g^,

Elution with petroleum ether - ether (5C:l) gave the starting

ketone (CVIIIj, (200 mgj, m.p. 142° (reportec^^, m.p. 140°C).


afforded (CXXXII) as an oil 'D* (520 mg). The compound shows

negative Beilstein test.

JD^^^ 3000 (aromatic), 1620 (C=C), 1580 (C=N), 755 cm~-'-(C-S).

d 7.2 (4H, m, aromatic protons), 6.6 (IH, ni, C4-H;, 6.3

(IH, m, C3-H), 2.4 (3H, m, C6-H2 and C8-H), 1.0, 0.95,

0.86, O.S, 0.7 (other methyl protons'.

Analysis founa : c, 81.2; H, 9.9; N, 2.7

^35^51'^^ requires : C, 81.18; H, 9.93; N, 2.7;:;.

Further elution witn petroleum ether - e-.her (I5:l)

: 121

afforded (CXXXIII) ( 00 mg) as noncrystallizable oil 'I;',

which gave positive Beiistein test.

5) 30CO (aromatic), 1610 (C=C), 1583 (C=N), 755 (C-S),

748 cm"-'- (C-Cl).

d 7.15 (4H, m, aromatic protons), 3.7 (IH, m, C3-Ha,

Wl/2 = l4Hz), 2.4 (3H, m, C6-H2 and C8-H), 1.08, 0.85,



C3^H^3NSC1 requires : C, 75.84; H, 9.46; N, 2.53%

Reaction of 7-oxostiqinast-5-en-3g-yl acetate (CIXJ with

2-aminothioDhenol ; 5a-Stigmastan-[5,7-bc]-2',3'-dihydro-

l* . 5' -benzothiazepin-as-vl acetate (CXXXV) :

A mixture of ketone (CIX) (1.5 g) and 2-aminothiophenol

(0.75 g) in absolute methanol (30 ml) having two drops of

cone, hydrochloric acid was refluxed under anhydrous condition

for three hours. The reaction progress was monitored by

TLC. Removal of the solvent under reduced pressure gave

(CXXXV) (680 mg) as noncrystallizable oil «F'. Which was

further purified by passing through a column of silica gel.

Elution with petroleu.-n ether - ether (15:1) gave the product

: 122 :

0

•£) 3C00 (aromatic), 1720 (CH^-C-O), 1620 (C=C), 1580 - nax • -J

(C=N), 1240 (acetate), 720 cm""'- (C-S).

d 7.15 (2H, m, aromatic, C9'-H, C6'-H), 6.56 (2H, m,

aromatic, C7'-H, C8'-H), 4.5 (IH, m, C3-Ha, Wl/2 = Q ti

17Hz), 2.4 (3H, m, C6-H2 and C8-H), 2.0 (3H, s, CH^-C-C),

1.1, 1.0, 0.92, 0.85, 0.76 (other methyl protons).


^37^55^^°2 ^^q^i^^s • C' 76.89; H, 9.59; N, 2.42.^.

7-Oxostiqmast-5--en-3g-vl propionate (CX) :

To a solution of cholest-5-en-3^-yl propionate (8 g) in

carbontetrachloride (150 ml), acetic acid (30 m l ) , and

acetic anhydride (10 ml) was added at 0°C, a solution of

t-butylchromate [from t-butyl alcohol (60 ml), chromium

trioxide (20 g ) , acetic acid (84 ml) and acetic anhydride

(10 ml)]. The mixture was heated under reflux for four hours

and the reaction mixture was diluted with cold water. The

organic layer was washed with water, sodium bicarbonate solu

tion (5%) anc again with water and dried over anhydrous sodium

sulphate. Evaporation of the solvent under reduced pressure

gave an oil which was crystallized from methanol to give (CX)

(3.2 g ) , m.p. 165 C. O

2) 1730 (C..H.-C-0), 1680 (-C=C-C=0), 1640 ( C=C ) cm"^

: 123 :

d 5 .65 (IH, s , C6-H), 4 . 2 (IH, b r s , C3-H.«,Wl/2 = ISHz),

2.38 (2H, q, CH3-CH2C-O), 2 .17 (3H, m, C4-H2, CS-Kj,

1.18 (3H, t , CH3CH2g-0), 1 .16, 0 . 9 5 , 0 . 8 0 , 0 . 7 5 , 0 .68

( o t h e r methyl p r o t o n s ) .

A n a l y s i s found : C, 7 9 . 3 ; H, 10.8

^32^52*^3 ^ e q ^ i ^ e s : C, 7 9 . 2 8 ; H, 10.81%.

Reaction of 7-oxostiqmast-5-en-36-vl propionate (CX) .vitr;

2-aminothiophenol ; 5a~Stiqmastan-[5,7-bc]-2*,3'-dihvciro-

1*.5*-benzQthiazepin-3g-yl propionate (CXXXIX; :

A mixture of enone (CX) (1,5 g) with 2-aminothiophenol

(0.75 g) in absolute methanol (30 ml) having two drops of

cone, hydrochloric acid was refluxed under anhydrous condi

tions for three hours. The reaction was monitored by TLC.

Removal of the solvent under reduced pressure gave iCXXXTA)

(675 mg) as an oil 'G' which Was further purified by silica

column and eluted with petroleum ether - ether (15:1).

^max. 2°6^ (aromatic), 1735 (C2H^'c-0-), 1620 (C=C), 158C

(C=N), 760 cm"- (C-S).

(^ 7.3 - 6.08 (4H, m, aromatic), 4.2 (IH, brm, C3-H,

Wl/2 =^l0Hz), 2.61 (3H, m, C6-H2, C8-H), 2.38 (2H, q,

" M CH3CH2C-O), 1.18 (3H, t, CH3CH2-C-O), 1.06, 0.95, 0.39, 0.75, O.oS (other methyl protons).

: 124 :


C H ^OoNS requires : C, 77.1; H, 9.71; N, 2.36 '. 38 57 ^

3.6-Dioxostiqma5t-4-ene (CXi) :

p-Sitosterol U © g) was suspended in acetone (300 ml)

in a three necked round bottom flask fitted with a stirrer

and a dropping funnel. The suspension was stirred for 30

minutes and then Jone's reagent (25 ml) was added drop^ise

from the dropping funnel in a course of 45 minutes. Tne

temperature of reaction mixture was maintained at O-5°C by-

external cooling. After the addition, was complete, stirring

was continued for additional 30 minutes and then cold water

(200 ml^ was added. The product was collected by filtration

and washed several times with water and air dried. The

crude product was crystallized from acetone to give the

^ CXI) (2.2 g) m.p. 156° (reported^^, m.p. 156^).

Reaction of 3.6-dioxostiamast-4-ene (CXI) with 2-aminothio

phenol ; 3-Oxo-5a-stiamastan-l 4a.6-bc 1-2'.3*-dihvdro-l\ 5'-

benzothiazepine (CXLJ :

A mixture of enedi6ne(CXl) (1.5 g; with 2-aminothiophenol

(0.75 g) in absolute methanol (30 mi; having two drops of cone,

hydrochloric acid, was refluxed under anhydrous conditions for

: 125 :

five hours. Tne reaction was monitored by 7LC. Removal of

the solvent uncer reduced pressure gave an oil Cl«3 g)

which Was cnronatographed over silica gel^ Elution with

petroleum ether - ether (15:1) gave an oil 'H', which coulo

not be further analysed due to the lack of quantity Further

elution wi^h same solvent (12:IJ gave CXL as an oil I (750 mg)

which coula not be crystallizBd,

i ^ ^ 300C, 162C (aromatic;, 1705 (C=0), 1552 (C=N), 755 cm""

(c-s).

d 6 .4 (4H, m, a romat i c p r o t o n s ) , 5 .6 (14, d, C4-H), 3 .0

(IH, 21, C5~H), 2 . 1 (4H, m, C2-H2, Cl-H^), 1 . 1 , 1.0,

0 . 9 5 , 0 . 8 , and 0 . 7 (o the r methy l p r o t o n s ) .

A n a l y s i s found : C, 7 8 . 7 ; H, 9 . 6 ; N, 2 . 6

^ 3 5 ^ 5 1 ° ^ r e q u i r e s : C, 7 8 . 7 4 ; H, 9 .62; N, 2.62%

3^titvmtti

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127 :

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: 128 :

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: 129 :

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Cbapttr-tElirce (S)

STEROIDAL ARYLIDENES

tEêoretical

In 1965 Christiansen et al. first reported the

preparation of l6-arylidine derivatives of androstanes and

androstenes which exhibit anabolic, androgenic, pituitary-

inhibiting, coronary dilatory and antihypertensive activi

ties. A large number of 16-arylidene derivatives of

5-androsten-3p-ol-17-one (I) and of androstan-3p-ol-17-one

(XVl) were prepared by reactionîn refluxing methanolôf the

appropriate aldehyde in the presence of an equivalent amount

of KOH. They prepared l6-(2,4-dichlorobenzylidene)-5-androsten-

3^-ol-17-one (III; by the reaction of 5-androsten-3^-ol-

17-one (I) and 2,4-dichlorobenzaldehyde (li;.

( i ;

CHO

( i i i ;

: 123 :

16-(2-Pyridylmetnylene)-5-androsten-3^-ol-17-one (Vj was

preparea by the conoensation of I and picolinaicehyce (IVJ

^ N CHO

CIV) CV)

16 -C4-Methoxybenzy l idene ) -5 -andros t en -3p-o l -17 -Dne

t V I I j , was p repa red by t h e condensa t i on of I anc 4 - -e tnoxy-

benza ldehyde ( V I ) . . ^ ^ ^ - 3

OCH-

I + -> P

CHO ^ (VI) (VI I ;

They p repa red l6-(4-dimethylaminobenzyl ideneJ-f ,—

a n d r o s t e n - 3 ^ - o l - 1 7 - o n e (IX) by t h e r e a c t i o n of I witr.

4-aime-cnyldminobenzaldehyde (VI I I J .

CHO

( V I I I ) (IX)

: 134 :

1 6 - l C i n n a r r . y l i d e n e ) - 5 - a n d r o s t e n - 3 p - o l - 1 7 - o n e (XI) waj

p r epa red by t h e r e a c t i o n I v/ith c innamalcehyde (X) .

CH=CH-CHO

I + j s

CH-CH = CH V) (x;

(XI ;

l 6 - ( 2 - M e t h o x y b e n z y l i d e n e ) - 5 - a n d r o s t e n - 3 ^ - o l - 1 7 - o n e

( X I I I ) Was p r e p a r e d by t h e r e a c t i o n of I with 2-methoxy-

benza ldehyde ( X I I ) .

I +

CHO

(xii;

0

" ^

H

(xiii;

16-(4-Pyridylmethylene)-5-androsten-3p-ol-17-one (XV)

was prepared by the reaction of I with isonicotinaldehyde

(XIV).

CHO

I + — >

txivj (x^/)

: 135

15-l,4-M5thoxybenzylidene)-5a-androstan-3p-ol-17-one

(XVIl) was prepared by the condensation of androstan-3^-ol-

17-one (XVI) with 4-niiethoxybenzaldehyde (Vl) .

OCH,

->

(xvi; (VI) (x^/ii)

They prepared l6- (2-pyr idylmethylene) -5a-andros tan-

3^-ol-17-one (XVIIl) by the condensation of XVI with IV.

XVI + ^ ^ H O

-^

(IV) (xviii;

16-(4-Pyriaylmethylene)-5a-androstan-3p-ol-17-one

(XIX) was prepared by the condensation of XVI with XIV,

CHO

XVI -»

(XIV) (XIX)

130 :

1 6 - ( 4 - D i m e t h y l a m i n o b e n z y l i d e n e ) - 5 a - a n c r o s t a n - 3 £ - o l -

17-one (XX^ was p repa red by t h e r e a c t i o n of X!l witr. V I I I .

-CHs

CHO

XVI + ^ v .

( V I I I ) (XX;

They also prepared l6-(4-benzyloxybenzylidene}-5a-

androstan-3p-ol-17-one (XXIl) by the reaction of X'v'I with

4-benzyloxybenzaldehyde (XXI).

CHO

XVI

/ r \ ; ^ H Ph

0CH2Ph

(xxi;

^ v (XXII;

•J

Akio and H i r o s h i p repared a - ( 3 , 5 - d i b r c x o - 2 - h y a r o x y -

p h e n y l j - p - b e n z o y l - ^ - c y a n o e t h y l e n e (XXV) by the condensa t ion

of b e n z o y l a c e t o n i t r i l e (XXIV) wi th 3 ,5 -d ib ro .T iOsa l i cy la l -

dehyde (XXIIIJ i n pxesence of ammonium acetate in benzene.

B r ^ ^ r v r ^ H O

H

0

+ CHo-t-Ph I ^ CN

-> - Ph

(xxiii; (XXIV) (XXV)

: 137 :

Essaw/ et al. prepared XXVIII by the reaction of XXVI

with 2,4-pentadione (XX^/II).

"3= >7-

CH^ 0 I ^ II

H3C^ C-CH2-C-CH3

N \ N ^ 0

Ph

+ CHo-C-CHo-C-CH^-3 ,, 2 ,, 3 O 0

N I Ph

(XXVI j (xxvii; (XXVIII)

Condensation of XXVI with benzil (XXIX) afforaed XXX.

CH-CH3 I '

J^ V '^ Ph-C-C-Ph -> N O

I Ph

(XXVI)

0 O

(XXIX)

<^f^c I Ph

Ph Ph

N / t Ph

(XXX)

They also preoared XXXII by the condensation of XXVI

with XXXI.

C - C H = CHV y-0CH3

^

(XXXI) XXVI

«3^' C-CH =C OCH,

i h

iXXXIl)

: 138 :

4 Gunushchak et al. preparea XXXV by the condensation

of XXXIII with acetaldehyde (XXXIV).

(XXXIII)

CHO + CH3CHO

(XXXIV) (XXXV)

5 Lian Niang Li et al. synthesized the mutasterol

(24-methylene-25-ethylcholesterol) (XXXIX), which is a miner

component of the sterol fraction of the sponge Xestospongis-

muta. The aldol condensation of XXXVI and 3,3-dimethyl-2-

pentanone (XXXVIl) at -70° in presence of lithium diisopro-

pylamide yielded the (22E)-25,26-dimethyl-6p-nethoxy-3a,5-

cyclocholest-22-en-24-one (XXXVIII) which was transformed to

mutasterol (XXXIX).

OCH^

(XXXVI)

^ ->

0 CHo II I

CH.-C-C-CH -CH^ 3 I 2 3

CH3

(XXXVIl)

-»

(XXXVIII)

(XXXIX)

: 139 :

m

R a j e n d r a P r a s a d e t al.*^ p r e p a r e d 9 - m e t h o x y - 2 , 6 , c - t r i -

e x h y l - 7 , 3 - d i h y d r o - 4 H , 6 H - b e n z o , ^ l , 2 - b : 3 , 4 - b ' J d i p y r a n — i - o n e

( X L I I j by t h e c l a i s e n c o n d e n s a t i o n of 8 - a c e t y l - 7 - h y d r o x y - 5 -

m e t n o x y - 2 , 2 - d i m e t h y l c h x o m a n (XL) w i t h e t h y l a c e t a t e (XLI)

i n t h e p r e s e n c e of sodium m e t a l .

+ CH3-C-0Et

OCH-

(XL) (XLI) (XLI I )

They a l s o s y n t h e s i z e d 5 ~ m e t h o x y - 2 , 8 , 8 - t r i m e t h y l - 9 , 1 C ~

d i h y d r o - 4 H , 8 H - b e n z o [ l , 2 - b : 5 , 6 - b ' ] d i p y r a n - 4 - o n e (XLV) cy t h e

c o n d e n s a t i o n of 6 - a c e t y l - 5 - h y d r o x y - 7 - m e t h o x y - 2 , 2 - d i n : e - : h y l -

chroman ( X L I I I ) w i t h XLI i n t h e p r e s e n c e of sodium r . e t a l .

OCH- O

+ CH loEt C ^ ^^-3

(XLI)

(XLr/)

: 140 :

5-Methoxy-2, 8, 8 - t r i m e t h y l - 6 , 7-cihy(iro-4H, 8H-benzo

[ l , 2 - b : 5 , 4 - b ' ] d i p y r a n - 4 - o n e (XLVI) was prepared by t h e

c l a i s e n c o n d e n s a t i o n of 6 - a c e t y l - 7 - h y d r o x y - 5 - m e t h o x y - 2 , 2 -

dimethylchroman (XLV) wi th XLI in t h e presence of sodium ,6

me ta l .

0 11

CH3-C-0Et

(XLI) (XLVI)

El-Kady e t a l . prepared XLVIII by c l a i s e n condensa

t i o n of XLI with 6 - a c e t y l - 7 - h y d r o x y - 4 - m e t h y l coumarin

(XLVII) fol lowed by c y c l i z a t i o n . The product XLVIII wi th

benza ldehyde (XLIX) gave L.

(XLVII)

+ CH -C-OEt

(XLI)

[ ^ (J + XLVI I I

CH^-C-CH-2 II 3 0

(XLVIII)

0 k\

CH^CCH = CH

(XLIX) (L)

: 141 :

They also syntnesized LII by claiscn condensation of

ethyl acetdte(XLI) with 8-acetyl~7-hydroxy-4-methyl coumarir.

(LI).

0-^0

O

+ CH3-C-0Et

(XLI)

8

CH^-C-Cr.^

0^"0

(LII)

Dawidar et al. reported the formation of IX which

was already reported and supported the structure by

spectral values. They also preoared l6-(4-nitrobenzylidene}

-5-androsten-3^-ol-17-one (LIV) and 16-(2-nitrobenzylid<»ne)-

5-androsten-3^-oI-17-one (LVI) by the reaction of I with

4-nitroben2alaehyde (Llil) and 2-nitrobenzaldehyde (LV).

I + ->

(LIV)

: 142 :

CHO

I +

(LV) (LVI)

Nico lae e t a l , prepared LIX by t h e condensa t ion of

2-.-nethylpropanol (LVII I ) with 4-methylcyc lohexanone (LVIIj

i n NaOH-MeOH.

+ ^H-CHO H3(/

(LVII) (LVIII) 10

CH3

H3C V" CH-,

CH-CH^ CH.

(LIX)

Roska et al, prepared LXI by the condensation of

4-nitrobenzaldehyde LIU with ethylcyanoacetate (LX).

CHO

II -t- CH,-C-OEt

c^N^y

(LIU) (LX)

CH=(j:H-C-OEt CN 0

(LXI)

Zooroh and Hamama prepared LXIII and LX/ by tr.e

c o n d e n s a t i o n of LXII with e t h y l a c e t a t e (XLl) and d i e - . - y l -

o x a l a t e (LXIV) r e s p e c t i v e l y .

if + CH3-C-0Et

0 C 0

^•C,C-CH2-C-CH

1 1 H

(LXII)

O II (LXII) + C-OEt I C-OEt II o

(LXI) (LXIII )

• »

(LXIV)

(LX.-) Osipowicz e t al."^^ s y n t h e s i z e d 2-methyleneandros-:a—i,

6 - d i e n e - 3 , 1 7 - d i o n e (LXVIIi; by t h e r e a c t i o n of a n d r o s - a - ^ ,

6 - d i e n e - 3 , 1 7 - d i o n e (LXVI) with formaldehyde (LXVIIj .

Q

12

(LXVI) (LXVII) (LXVIII)

: 1'

13 Dryanska et a l . " " synthesized LXXI in 41-47,^ yiel(

by the condensation of benzylbenzothiazole (LXIX) with

RCHO (LXX; in presence of NaOH.

S

If VC=CHR ^ Ph

(LXIX) (LXX) (LXXI)

R R

( a ) Ph ( a ) Ph

(b) Substituted Ph (b) Substituted Ph

(c) a or ^-C^^^j (c) a or ^-C^^^j

MsitnUfim

A survey of literature revealed that very few steroidal

arylidene derivatives have been prepared. Some of them are g

of medicinal values . In view of these observations some

easily accessible ketones in the cholestane series had been

selected as substrates for the synthesis of hitherto

unknown steroidal arylidenes.

The ketones, 3-oxocholest-4-ene (LXXIl), 5,6p-dibromo-

3-oxo-5a-cholestane (LXXIIl), 3-oxocholesta-4,6-diene (LXXIV)

and 3,6-dioxocholest-4-ene (LXXV), were allowed to react with

4-N,N-dimethylaminobenzaldehyde (VIIl) and the products

obtained have been characterized on the basis of their elemental

analysis and spectral properties.

(LXXII)

: 14;

(LXXIV; (LXXV)

Reaction of 3-oxocholest-4-ene (LXXIl) with 4-N,N-ciimethvl-

aminobenzaldehyde (VIII) : 2-(4*-N.N-Dimethylaminobenzylidene)-

3-oxocholest-4-ene (LXXVI) :

3-0xocholest-4-ene (LXXII) was allowed to react with

4-N,N-dimethylaminobenzaldehyde (VIIl) at room temperature.

Usual workup of the reaction mixture afforded a solid product

decomposed at 280 , The product,analysed for C^^H-^ON ,

showed the presence of arylidene moiety in the product.

^8^17

H-jC CHo

- ^

o-^-^^^^^

(Lxii; (LXXVI)

• * 7 • • —^ ' •

Its i.r. spectrum showed absorption bards cit 3000 cm

for aromatic protons. The broad band from 1580 to 1615 cm

showed the presence of more than one carbon-carbon double

bond. Bands at 1660 cm" indicated the presence of conju-15

gated carbonyl group; most likely it was a case of cross-

conjugated carbonyl group as present in the structure (LXXVI).

d i. CH,

D group (-N<

vely,

Bands at 1375 and 805 cm" showed the presence of tertiary

3 8 amino group (-N<pLr ) and parasubstituted benzene , respecti-

The n.m.r. spectrum of compound (LXXVl) displayed two

multiplets at d 7.17 integrating for three protons assigned

to C2'-H, C6'-H and =CH-Ar and d 6.64 for two protons

ascribable to C3'-H and C5*-H (4 aromatic protons + 1 vinylic

proton). A broadened signal at d 6.08 integrating for one

proton assignable to C4-vinylic proton. A singlet at d 2.98

integrating tor six protons had been assigned to protons of

2-methyl groups attached to nitrogen. Other methyl protons

gave signals at d 1.21, 0.89, 0.81 and 0.75 .

Therefore in accordance with the composition, spectral

properties and by precedence the compound (decomposed at

280°) can be characterized as 2-(4«-N,N-dimethylaminobenzyli-

dene)-3-oxocholest-4-ene (LXXVl).

: 148 :

Reaction of 5,6g-dibromo-3-oxo-ba-cholestane (LXXIIl) with

4-N.N-dimethyIaminoben2aldehyde (VIII) : 2-(4*-N,N-Dimethvl-

aminobenzylidene)-3-oxocholesta-4,6-diene (LXXVIl) r

The dibromoketone (LXXIIl) was allowed to react with

4-N,N-dimethylaminobenzaldehyde (VIII) at room temperature.

Usual work up of the reaction mixture gave a single produce

as a solid m.p. 211°. The product analysed for C H j ON

compatible with the structure (LXXVIl). Negative Beilsteir.

test and analysis suggest that both the bromine atoms have

been eliminated in the reaction process.

^8^17

"3V^"3

(LXXVIl)

The i.r. spectrum of the compound, m.p. 211° showed

bands at 3000 cm"! (aromatic), 1665 (C=0 group in conjugatation 1 e. Chi

With C=C), 1600 (C.C)1^ 1375 (-N<^^^), and 805 cm'^

(parasubstituted benzene).

: 149 :

The n . n . r . spectrum of the compound shO''.ed multiole-t

a t d 7.71 i n t e g r a t i n g for three protons ascr ibable to C2'-H,

C6*-H and =CH-Ar . The broad s i n g l e t a t d 6.65, i n t eg ra t i ng

for two protons assigned t o the remaining two a rona t ic protons

Another mul t ip le t a t d b .35, i n t e g r a t i n g for th ree protons was

assigned to t h r ee v iny l ic protons i . e . , C4-H, C6-H and C7-H.

Two methyl groups a t nitrogen gave a broad s ing l e t at d 3.06.

Other methyl s i g n a l s were observed at d 0.87, 0 .8 , 0.68

These values can best be r a t i o n a l i z e d by considering

the s t r u c t u r e (LXXVIl) for the compound which can be

t e n t a t i v e l y cha rac t e r i zed as 2-(4*-N,N-dimethylaminobenzyli-

dene)-3-oxocholes ta-4 ,6-d iene (LXXVIl).

Reaction of 3 -oxccholes ta -4 .6-d iene (LXXIV) with 4-N.N-di-

methvlaminobenzaldehyde (VIIl) ; 2-(4*N^N-Dir.ethylcminobenz^JJ.-

dene)-3-oxoc.- .oles-a-4,6-dien-3-one (LXXVIl) :

The dienone (LXXIV) was allowed to react with 4-N,N-

dimethylaminooenzaldehyde (VIIl) at room temperature. Final

work up of the reaction mixture gave a single product as a

solid m.p. 211°.

: 150 :

' T ^ ^ ^ ^ 0 ^ ^ ^ ^

(Lxxiv; (LXXVII)

The solid, m.p. 211° was analysed for C3 Hp j 0N with

negative Beilstein test. This solid material was identical

with the product obtained from the dibromoketone (DCXIIl)

(m.p., mixed m.p., TLC, Co-TLC, and spectral properties).

Reaction of 3.6-dioxocholest-4-ene (LXXV) with 4-N,N-dimethyl-

aminobenzaldehyde (VIIl) : 2-(4'-N,N-Dimethylaminobenzyliaene)-

cholesx-4-ene-3.6-dione (LXXVIIl) :

17 3,6-Dioxocholest-4-ene (LXXV) was allowed to react

with 4-N,N-dimethylaminobenzaldehyde (VIII) at room tempe

rature. Final work up of the reaction mixture gave single

product as a solid which decomposed at 260°. The solid,

analysed for C^^H^^^O^M, showed the presence of arylidene

moiety in the product.

: 151 :

0/

C«H 8»17

(LXXXV) (LXXVIII)

The i.r. spectrum of the compound showed broad band at

1670 cm*" which indicated the presence of two carbonyl groups

-1 inconjugation with the double bond. A band at 1613 cm" was

assigned to carbon-carbon double bonds (C=C) . Peaks at

1370 and 810 cm" showed the presence of tertiary amino group

CH-— 3 8

(-N< ) and parasubstituted benzene respectively. On the

CH3

basis of molecular composition and i.r. spectra two struc

tures can be proposed for the compound under discussion.

The n.m.r. spectrum of the compound showed a multiplet

at 6 7.65 inzegrating for three protons which can be assigned

to the protons of C2'-H, C6'-H and =CH-Ar. The broad multi

plet dt d 7.23 integrating for two protonswas ascribed to the

: 152 :

^ 3 ^ CH-N

7X? 0

(LXXyill)

CH^

H-f\^ \ / 3

(LXXIX)

remaining two aromatic pjrotons. A broadened singlet at

d 6.61 for one proton indicatedthe presence of a vinylic

hycrogen at C4. Singlet at d 3.0 integrating for six protons CH3

was characteristic of two methyl groups of N<pij, Other methyl

16 protons gave signals at 0 0.88, 0.83, 0.76 and 0.68 .

On the basis of spectral data it was not possible

to distinguish between the two structures (LXXVIII) and

(LXXIX). However, the structure (LXXVIII) is preferred on

steric considerations.

Thus on the basis of the above facts the compound,

m.p. 260 (decomp.) can be tentatively formulated as 2-(4*N,M-

dimethylaminobenzylidene)cholest-4-ene-3,6-dione (LXXVIIl).

experimental

5.6B-Dibromo-5a-cholestan-38-ol

To a solution of cholesterol (14 g) in ether (100 ml)

was added gradually bromine solution (9.6 g of bromine in

100 ml of glacial acetic acid containing 1.0 g of anhydrous

sodium acetate) with stirring. The solution turned yellow

and promptly set to a stiff paste of the dibromide. The

mixture was cooled in an icebath and stirred with a glass

rod to ensure complete crystallization. The product was then

collected by filtration under suction and washed with cold

ether-acetic acid mixture (3;7) until the filterate was

completely colourless. The solid obtained was air dried to

give 5,6^-dibromo-5a-cholestan-3^-ol (15 g), m.p. 112-113°

(reported , m.p. 113°C).

5.6e-Dibromo-3-oxo-5a-cholestane (LXXIII) ;

The bromide (10 g) was suspended in acetone (300 ml) in

: 154 :

a three necked round bottom flask fitted with a stirrer and

dropping funnel. The suspension was stirred for 5 minutes

and Jone's reagent (15 ml) was added drcpwise in 15 minutes.

The temperature of reaction mixture during oxidation was

maintained between 0-5° by external cooling. After the

addition was complete stirring was con-inued for 15 minutes

and cold water (200 ml) was added. The product was collected

on a Buchner funnel and washed thoroughly with water and

methanol and air dried to give the dibronioketone (LXXIIl)

(8 g), m.p. 73° (reported"^^, m.p. 73-75°C).

3-Oxocholest-5-ene :

To a solution of dibromoketone (LXXIIl) (5 g) in ether

(100 ml) and acetic acid (2.5 ml) was acaed zinc dust (7.5 g)

in small portions during 30 minutes with continuous shaking.

After complete addition the ethereal solution containing

suspended zinc dust was filtered in separating funnel. The

ethereal phase was then washed with water and dried over

anhydrous sodium sulphate. The oily residue obtained on

evaporation of the solvent was crystallized from methanol to

give the desired product (3.5 g), m.p. 117-128° (reported"'-' ,

m.p. 129°C).

: IcD :

3-Q>och3lest-4-ene (LXXIl) :

A solution of 3-oxocholest-5-ene (5 g) in etnanol

(50 ml) containing oxalic acid (0.6 g) was heatec uncer

reflux for 15 minutes. The reaction mixture was poured

into water and extracted with ether. Ether extract was

washed with water and then dried over anhydrous sodium

' sulphate. Evaporation of the solvent left oily residue

which was crystallized from methanol in the cold to give

the ketone (LXXIl) (3.7 g), m.p. 80° (reported ^^ m.p.

81-82°C).

Reaction of 3-oxocholest-4-ene (LXXIl) with 4-N. N'-dimethyl-

aminobenzaldehyde (VIIl) ; 2-(4'N,N-Dimetb.ylaminccenzvlidene)'

3-oxocholest-4-ene (LXXVI.) :

A mixture of ketone (LXXIl) (0.5 g) anc the aldehyde

(0.291 g) (VIII) was treated slowly with socium hydroxide

in ethanol (4%, 3.25 ml). The reaction mixture was stirred

for 15hours left overnight at room temperature, ar.d the

resultant mixture diluted with water (50 ml), acicified with

dil. HCl. The solid obtained was filtered and recrystallized

from methanol to give (LXXVI ) (0.35 g) which decomposed at

280°C.

^max. ^^^^ (C=0), 1615 (C=C), 1375 (t-amine), 805

(p-substituted benzene) cm~^.

: 156 :

d 7.17 (3H, m, C2'-H, C6'-H, =CH-Ar), 6.64 (2H, brs,

[< CH

CH C3'-H, C5'-H), 6.08 (IH, s, C4-H;, 2.98 (6H, s, -N< ^^),

1.21, 0.89, 0.81, 0.75 (methyl protons).


^36^53^^ requires : C, 83.82; H, 10.36; N, 2.12%,

Reaction of 5^6g-dlbromo-3--oxo~5a-cholestane (LXXIII) with

4-N.N-dimethvlaminobenzaldehvde (VIII) ; 2-C4'N,N-Dimethvl-

a^linobenzylidene)-3-oxocholesta~4. 6-diene (LXXVII) :

A mixture of dibromoketone (LXXIIl) (5 g) and the

aldehyde (VIIl) (2.05 g) was treated slowly with sodium

hydroxide in ethanol (4^; 22.5 ml). The reaction mixture

was stirred for 28 hours left overnight at room temperature

and the resultant mixture diluted with water (50 ml) acidi

fied with dil. UCl. Ihe organic matter was extracted with

chloroform and the solution washed several times with water

and dried over anhydrous sodium sulphate. Evaporation of

the solvent afforded the compound 2-(4'^;,N-Dimethylaminobenzyli-

dene)-3-oxocholesta-4,6-diene (LXXVII ) which was crystallized

from methanol (3.4 g), m.p. 211°C.

i^max. ^665 (C=0}, 1600 (C=C), 1375 (t-amine), 805 cm"^

(p-substituted benzene).

: 157 :

d 7.71 (3H, m, C2'-H, C6'-H, =CH-Ar), 6.65 (2H, br,

C3'-H, C5'-H), 5.35 (3H, m, C4-H, C6-H, C7-H), 3.06 CH.

CH.

CH (6H, s, -N< ), 0.87, 0.8, 0.68 (other methyl protons)

'3


CO.H^-TON requires : C, 84.15; H, 10.01; N, 2.73%. 36 O'

3-0xocholesta-4.6-diene (LXXIV) :

To a solution of 5,6p-dibromo-3-oxo-5a-cholestane

(LXXIII) (5 g) in dimethylformamide (50 ml) was added

lithium chloride (1 g) and the reaction mixture was heated

under reflux forlhourand then poured into water and extrac

ted with ether. The ethereal layer was washed with water,

sodium bicarbonate solution (55 ) and water and dried over

anhydrous sodium sulphate. Removal of the solvent gave an

oil (4.5 g) which was chromatographed over silica gel (100 g).

Elution with Petroleum ether-ether (12:1) and crystalli

zation from metnanol afforded 3-oxocholesta-4,6-diene (LXXIV)

(2.5 g), m.p. 79° (reported"^^, m.p. 79-80°C).

Reaction of 3-oxocholestq-4.6-diene (LXXIV) with 4-N.N-

dimpthvlaminobenzaldehvde (VIII) ; 2-(4'N,N-Dinietnylamino-

benzylidene)-3-oxocholesta-4T 6-dieneCLXXVII ) :

A mixture of ketone (LXXIV) (2 g) and the aldehyde

: 153 :

(VIIl) (1.0 g) was treated slowly with socium hydroxide in

ethanol (4%; 11 ml). The reaction mixture was stirred for

17 hours left overnight at room temperature and the resultant

mixture diluted with water, acidified with dil. HCl. The

organic matter was extracted with chloform and the solution

washed several times with water (50 ml) and dried over sodium

sulphate. The oily residue obtained on removal of solvent

was crystallized from methanol to give (LXXVII ), m.p. 211°.

This was found to be similar in all respects with the product

(LXXVII ) obtained from 5,6p-dibromo-3-oxo-5a-cholestane

(LXXIII) under similar reaction conditions.

Reaction of cholest~4~ene-3.6-dione (LXXV ) with 4-N.N-

dimethylaminobenzaldehvde (VIIl) ; 2-(4*/hf»N-Dimethvlamino-

benzylidene)cholest-4-ene-3.6-dione (LXXVIII) :

A mixture of ketone (LXXV ) (1.24 g) and aldehyde

(VIII) (0.696 g) was treated with sodium hydroxide in

ethanol (4%; 8 ml). The reaction mixture was stirred for

23 hours left overnight at room temperature, and the resultant

mixture diluted with water (50 ml), acidjfied with dil. HCl.

The organic matter was extracted with chloroform and the

solution washed several times with water and dried over anhydr

ous sodium sulphate. Evaporation of the solvent and recry-

stallization of the residue from methanol gave LXXVIII which

decomposed at 260°C.

A 1670 (C=0;, 1613 CC=C), 1370 (t-air.ine), 810 cm"" ^^ /H3X •

(p-substituted benzene^.

7.65 (3H, m, C2'-H, C6'-H, =CH-Ar), 7.23 (2H, brs, C3'-H, CH,

CH,

CH C5«-H), 6.61 (IH, m, C4-H), 3.0 (6H, s, -N< ^ ) , 0.88,



36 51 2 ^ requires : C, 81.61; H, 9.70; N, 6.04%,

d^tltnnttsi

1. R.G. Christiansen, R.O. Clinton and J.W. Dean, U.S.

Pat 316341 (1964); Chem. Abstr., 62, 7834h (196b).

2. S. Akio, M. Hiroshi, J. Org. Chem., 34, 3612 (1969).

3. A. Essawy, Y.M. Elgarby and A.Z. Haikall, Pak. J. Sci.

Ind. Res., 20(3). 129 (1977); Chem. Abstr., 90,

152069a (1979).

4. N.I. Ganushchak, V.A. Barauor and V.A. Vengrazhanovski;

Chem. Abstr., £2, 198193f (1980).

5. L.N. Li, Sjoestrand and C. Djerassi, J. Am. Chem. Soc,

103(1), 115 (1981).

6. K.J. Rajendra Prasad, C.S. Rukmani Iyer and P.K. Iyer,

Ind. J. Chem., 22(B). 168 (1983).

: 161 :

7. M. El-Kady, M.K. El-Deck, R.M. Saleh and M.G. El-Dein,

Rev. Roum. Chim., 28(9-10). 915 (1983); Chen. Abstr.,

101. 38306W (1984).

8. A.M. Dawidar, M.A. Metwally, P.M. Abdel Galil and M.A.

Berghot, Ind. J. Chem., 24(B). 1124 (1985).

9. B. Nicolae, C. Olga, B. Emilia, S. Moga-Cheorghe and

Z. Dinu, Rev. Chim., 36(6). 485 (1985); Chem. Abstr.,

103, 2l4334f (1985).

10. A. Roska, M. Klavins, S. Eiduka, A. Veveris and A.

Zicmanis, Latv. FSR Zinat. Akad. Vestis Kim. Ser.,

(5) 625 (1986); Chem. Abstr., 107, 96029t (1987).

11. H.H. Zooroh and W.S. Hamama, Pharmazie, 41(9). 630

(1986); Chem. Abstr., 23280h (1987).

12. B. Osipowicz, L. Tablonski and M. Stanislaw, Pol. J.

Chem., 60(1-3). 311 (1986).

13. V. Dryanska, Kh. Ivanov, Is. Kirilova and L. Shishkova,

Khim. Fuk. 79, 318 (1985); Chem. Abstr., 1]A, 42625k

(I99i;.

14. L.F. i-ieser, J. Am. Chem. Soc., 75, 5421 (1953).

: 162 :

15. R.M. bilverstein, C.C. Bassler and T.C. Merrill

'Spectrometric Identification of Organic Compound*,

John Wiley and Sons (1981).

16. N.S. Bhacca and D.H. Williams, *Applications of NMR

Spectroscopy in Organic Chemistry', Holden-Day, Inc.,

(1964).

17. A.H. Milburn, E.V. Truter and W.P. Woodford, J. Chem.

Soc, 1740 (1956).

18. L.M.F. Serpo, W. Wanderly and E. Florio, An Acad,

Brasil Cienc, 44, 410 (1972).

Cjiapter-tlTftree (5i)

SOLID SURFACE REACTIONS

Cdeoretical

Alumina and silica gel being good adsorbents, provide

a reaction site for various interesting transformations. It

also provides a reactive surface for the chromatographic

conversion of one functional group into another. A brief

summary is given below in chronological order covering the

recent examples of interest.

In 1943 Ott and Reichstein observed that bromohydrin

(l) when passed through a column of alumina provided the

epoxide (ll). This is followed by a number of other examples

illustrating the chemical transformations on solid surfaces.

AcO

(I)

OCXH,

->

AcO"""

(II)

COOCH,

: 16^ :

Sarett has observed two interesting reactions of the

steroidal cyanohydrin (III). When III was passed through

acid washed alumina column, on dehydration, unsaturated

nitrile (r/) was obtained, whereas a column of alkaline

alumina caused the elimination of a molecule of HCN to gene

rate the ketone (V) in 90? yield.

CH2R2

Reich et al. performed the reaction of 3p-tosyloxy-

5-hydroxy-5a-cholestan-6-one (Vl) with dry alumina in

pyridine and reported the formation of 5-hydroxy-5a-cholest-

2-en-6-one (VIl).

.65 :

TsO HO '6

(VI) (VII)

Soloway et al.* have observed the isomerization cf the

17a,20p-epoxyallopregnane-3p,20a-diol diacetate (VIII) to

3p,17^-diacetoxyallopregnane-20-one (IX) by chromatography

on silica gel, the same conversion is also reported to

occur at high temperature.

OAc

>

(VIII) (IX)

Leeds et al. have reported the analogous conversion

of l6a,17a-epoxyandrostane-3^,17^-diol diacetate (X) by

chromatography over silica gel to 3^,l6a-diacetoxyandrcstane.

17-one (XI), by heet also similar change occurs^.

: 16c :

AcO

AcO

.^CAc

(X) (XI)

Cremlyn and Shoppee^ reported that 7p-toluene-p-sulpho-

nyloxy-5a-cholestane (XIl) is partly decomposed by neutral

aluminium oxide in pentane to give 5a-cholest-7-ene (XIIl)

along with 5a-cholestan-7a-ol (XIV).

(XII) (XIII) (XIV)

7 Peterson and Chen reported the reaction of cholest-

4-en-7/S-ol benzoate (XV) on alumina column with chromium

trioxice and obtained 3-oxocholest-4-en-7^-ol benzoate (XVl).

Ic7 :

^8^17

(LXV)

8

(XVI)

Engel et al.° reported the transformation of ne-:nyl-4-

en-3-oxo-12a-tosyloxy-17a-methyletienate (XVIl) witn

4 11 collidine and alumina into methyl A ' -3-oxo-17a-.Tiet.hyl-

etiadienate (XVIII).

COOCH-

(XVII)

CCOCH3 CH-,

(xvii::

Biggerstaff and Gallagher obtained XX when tr.e

reaction of XIX was carried out on the alumina surface.

http://-3-oxo-17a-.Tiet.hyl-

: 165 :

AcO'

OAc AcO

(XIX) (XX)

Cholestan-3p-yl methyl sulphate (XXI) on contact with

neutral alumina column gave cholest-2-ene (XXIII) and

cholest-3-ene (XXIV) while cholesteryl methyl sulphate (XXIl)

under the same conditions gave cholesterol (XXV) and 3:5

cyclocholestan-6p-ol''"° (XXVI).

MeS020

(XXI) (xx:ii) (XXIV)

MeSO O

(XXII) (xx^/) OH

(XXVI)

: 169 :

SchL.tt and Tamm reported the elimination of acetic

acid from 3^,20p-diacetoxy-5a-pregnan-l~one (XXVII) when

it was passed through the alumina column and 20p-acetoxy-

5a-pregn-2-en-l-one (XXVIIl) was obtained.

Ac a

12 Douglas et al. reported the effect of alumina in

presence of methanol and potassium acetate on 3p-tosyloxy-

5a-cholestane (XXIX) and the elimination of p-toluene

sulphonic acid was observed to give XXIII . It is interest

ing to note that the other possible isomer (XXIV) was not

obtained.

?8' 17

TsO

: 170

13 Rowland and Nace reported that 3^-acetoxy-5,6p-

dihydroxy-5a-:holestane (XXXI) was obtained when the

corresponaing epoxide (XXX) was passed through the ethyl

acetate washed alumina column.

^8^17

HO T

14

Ac HO

OH

(XXXI)

Engel and Papadopoulos' ' reported that pregnan-12a-ol-

3,20-dione-12a-methyl sulfonate (XXXII) was treated with

aluminium oxide of pH 8.5 at 55°. There was obtained A

pregenene-3,20-dione (XXXIIl) by elimination of methyl

sulfonic acid. V/hile at room temperature starting material

was recovered.

MeSO^O

CH'

C=0

(XXXIIl)

; 17:

Henbest et al. obtained 2a-acetoxy-3-oxo-5a-cholestane

(XXXV') when 2^-acetoxy-3-oxo-5a-chole;>tane (XXXIV) was heated

with alumina for an hour. However both XXXT/ and XXXV on

prolonged duration gave isomer 3p-acetoxy-2~oxo-5a-cholestane

(XXXVI).

(XXXIV)

AcO,

XX) .16

H (XXXVI)

Namhara and Fishman reported the reaction of 3^,17a-

diacetoxy-16,17-oxido-5a,14p-androstane (XXXVIl) with acid

washed alumina and obtained 17-oxo-5a,14p-anGrostan-3p,16p-

diol diacetate (XXXVIII) and 17-oxo-5a, 14p-androstan-3p, 16;3-

diol-3-acetate (XXXIX).

AcO

AcO

(XXXVIl) (XXXVIII) (XXXIX)

: 172 ;

17 Bernoulli et al. carried out the reaction of alumina

in presence of acetic acid with cinobufotalon (XL) and

obtained anhydrocinobufotalon (XLl).

(XL) (XLI)

Several polyacetates were subjected to hydrolysis on

18 alumina by Johns and Jerina and demonstrated that the rate

of reaction allows clear distinction between the hydrolysis

of primary and secondary acetates. As an example 5a-furosta-

5,20(22)-diene-3^,26-diol diacetate (XLII) changes to 5a-

furosta-5,20(22)-diene-3^,26-diol-3-monoacetate (XLIIl) when

allowed to stand over on Alcoa-F-20-alumina for twenty hours

at room temperature.

AcO'

(XLII) (XLIII)

: 173

19 /

Chang reported tnat 12a-cholanol mesylateCcholest-

I2a~yl mesylate) (XLIV) on refluxing with alumina and

biological catalyst collidine gave 11-cholene (cholest-11-

ene) (XLV).

MeSO^ CgH^^

20 Stevanson reported the formation of ^-amyrin(olean-

12-en-3p-ol) (XLVIl) from a-amyrin (urs -l2-en-3p-ol) (XLVI)

when a solution of later is filtered through Woelm W-l-N

alumina. It is a case of 1,2-methyl shift under the conditions

(XLVI) (XLVII)

: 174 :

4 b

^ and ^ steroids with nitrosyl fluorj.de gave

5ci:-fluoro-4- and 6-nitrimine, which on chromatography over

alumina containing 6% water were converted into 5a-fluoro-4-

and 6-ketones respectively. Cholesteryl acetate (XLVIIl)

with excess NOF at O Cin methylene chloride gave 5a-fluoro-

6-nitriminocholestan-3^-yl acetate (XLIX) the benzene solution

of which on percolation through a neutral alumina (activity

III) column resulted in the formation of 5a-fluoro-3^-hydroxy-21

cholestan-6-one-3-acetate (L) . This process is known as

Boswell's procedure. 3^,17^-Dihydroxy-5-estrene-3,17-di-

acetate (Ll), under the same conditions gave 3p,17p-dihydroxy-

5a-fluoroestran~6-one-3,17-diacetate (LIl) .

CgHj_y

AcO'

(XLVIIl) (XLIX)

AcO

AcO

OAc

AcO

: l D :

(LI) (LID

Dimethyl-7-antihydxoxymethyl-2,3-diazabicyclo-[2,2,l]-

hept-5-en-2,3-dicarboxylate (LIV) was obtained by the

chromatography over Uoelm alumina (activity II) of dimethyl-

7-anti-N-nitrosobenzamido methyl-2,3-diazabicyclo-L2,2, l]

23 hept-5-en-2,3-dicarboxylate (LIIl)

(LIU)

_C02CH3

CO2CH3

l:i^CC^CH^

CO2CH3

(LIV)

24 Posner et al. reported that epoxy ring opening occurs

With alcohols, thiols and acetic acid in presence of dehydra

ted Woelm W-200 (Brockmann activity super I). The epoxide

(LV) gives corresponding 2-hydroxy alkylether (LVI)

: 176 :

2-hycixoxy a l < y l t n i o e t h e r (LVII) and 2-hydroxy

r e s p e c t i v e l y .

a c e t a t e ( - V I I I ) ,

k^Z OH

(LV) (LVI) OR (LVII) SR (LVII I ) OOCCH3

Mesyla te (LIX) in d ich lo romethane was t r e a t e d wi th

n e u t r a l aluminium o x i d e which gave methyl t r i q u i n a c e n e - 2 -

c a r b o x y l a t e (LX)

OSO^CH^ H3CO2C

(LIX) (LX)

Posner and Gurria reported that Woelm-W-200 neutral

alumina dehydrated at 400° and .06 Torr for twenty four

hours is a mild effective reagent for elimination of acyclic

and cyclic tosylates without any rearrangement eg. ianost-

8-en-3p-yl tosylate (LXI) was converted to lanosta-2,8-diere

(LXII).

: 177 :

TsO

2-Propanol on alumina reduces steroidal 3,6-, 3,11-

and 3,20-diones selectively at 3-positions. 3,6-Dioxo-5a-

cholestane (LXIIl) gives 3-hydroxycholestan-6-one (LXIV)

at 25°C after twenty four hours on alumina surface with

propanol 27

CgH-j_-7

(LXIII) (LXIV)

Alumina has been used at room temperature for high

yield dehydrosulfonation of some secondary cyclic and acyclic

and some primary sulfonate esters. For example, 10-pinnanyl-

: 178 :

tosylate (LXV) with alumina at room temperature gave ^-pinene

(LXVI), the product of a concerted 1,2-elimir.ation, some

a-pinene (LXVII), the product of 1,3-elimination and camphene

(LXVIII) suggested to be arising via a competing ionic

process >8

(LXV) (LXVIJ (D(VII) (LXVIIi;

Keinan and Mazur treated 3^-hydroxycholest-4-ene

(LXIX) with ferric chloride on a silica gel column and iso

lated cholesta-3,5-diene (LXX) in 90% yield from the eluates.

(LXIX) (LXX)

Nittala and Levie^"^ performed a reaction on withanolide

D (LXXI) using sodium chloride absorbed on silica gel and

reported the isolation of chlorohydrin (LXXII) and quinone

product (LXXIII) from the column.

: 179 :

.CH OH

(LXXII) (LKXIII) (LXXI) O 1

Kim e t a l . c a r r i e d out t h e e f f i c i e n t and s e l e c t i v e

c l e a v a g e of a c e t a l s ( e g . cyc lohexy l methyl t r i t y l ( t r i p h e n y l

me thy l ) e t h e r (LXXV) and k e t a l s (eg LXXVI) by us ing f e r r i c

c h l o r i d e absorbed on s i l i c a g e l and o b t a i n e d hydroxy compound

(UOCV) and ke tone (LXXVII) but c l e a v a g e of e t h e r i s p re fe r r ed

over k e t a l as shown i n eg LXXVIa which g i v e s LXXVIb.

(LXXIVJ I \ 0 . O

(LXXVIa)

Tr

(LXXVII)

OH

OH

(LXXVIIa)

: 180 :

32 Suarez and Mazzierl carried out the dehydro halo-

ger.ation of vicinal-dihaloalkenes (LXXVIIi; over silica eel

at 80°C in dark and obtained two isomers LXXIXa and LXXIXo.

Cfif- s - "r - •? - ^^e^s -Br Br

CLXXVIII)

— >

(LXXIXa)

H CKjBr

+HBr

(LXXIXb)

33 Corte and coworkers reported a convenient synthesis

of ketone imine (LXXXI) by dehydrocyanation of imidoyl

cyanides (LXXX) by passing in the gaseous phase (by evapora-

ting in vacuo; over solid potassium tert. butoxide at IIC'C,

CN I

R'-CH2-C = N-CH2R > R'-CH = C = N-CH2R

(LXXX; (LXXXI)

Ferreira and coworkers reported the oxidative

cleavage of carbon-carbon bond by using solid supported

potassium permanganate on silica gel, for example L<XXII

anc LJOCXIII gave LXXXIV and LXXXV respectively.

(LXXX11;

: 181

OAc OAc CCOH

"COOH

(Lxxxiii ;

35

(Lxxxv;

Nishiguchi et al.* " also reported the dehydration of

alcohols catalysed by copper (II) sulphate adsorbed on

silica gel as LXXXVI gives LXXXVII.Similar reaction was

29 earlier reported with other substrates

(LXXXVI )

* C0 (LXXXVII)

3p-Substituted-o-nitrocholest-5-ene when absorbed on

basic alumina at room temperature for fortyeight hours,

gave corresponding elimination products. 3^-Hydroxy-6-

nitrocholest-5-ene LXXXVIIIgave 6-nitrocholesta-3,5-diene

(LXXXIX) 36

: 1B2

H C / \ X ^

(DCXXVIII) (LXXXIX)

3 ^ - S u b s t i t u t e d - 5 , 6 a - e p o x i d e gave o l e f i n s over s i l v e r

n i t r a t e - a l u m i n a s u r f a c e , 3p-Hyclroxy-5,6a-epoxy-5a-37 c h o l e s t a n e (XC) gave c h o l e s t e r o l (XXV)

CgHj_7

(XXV)

Wfitusifim

30 Nittala and Levie reported the isolation of some

chlorinated withanolide from the plants Wihtania and Actinus

species and suggested that the chlorine atom in these

molecules was derived from sodium chloride present in the

plants. Therefore, they performed a model reaction on

withanolide 'D' (LXXI) using sodium chloride on active

support (silica gel) and the chlorohydrin (LXXIl) was

obtained along with some other products.

(LXXI)

,CH OH

(LXXII)

134 :

I n v iew of t h e above r e a c t i o n we c a r r i e d o u t t h e s a - e

r e a c t i o n on 3 f ? - h y d r o x y - 5 , 6 a - e p o x y - 5 a - c h o l e s t a n e (XC)

and 3 ; 3 - h y d r o x y - 5 , £ > a - e p o x y - 5 G - s t i g m a s t a n e (XCI) .

CoH 8"17 ^ 1 0 ^ 2 1

(XCI)

The products obtained have been characterized on the

basis of their spectral and chemical properties and offer

scope for stereochemical and mechanistic studies of the

reaction.

Reaction of 3;3-hycroxy-5,6a-epoxy-5a-cholestane ( XC)

with NaCI on silica gel ; 3-Oxocholest-5-en-6-yl chloride

(XCIi; 3,6-dioxo-5a-cholest^ne (LXIIIj. 5-hvdroxv-3-oxo-

5a-cholestan-6g-vl chloride (XCIII) :

38 The epoxide (XC) in absolute methanol was adsorced

over a pc- dered mixture of silica gel and NaCl (2:1), solvent

was evaporated cind the dry residue was heated at 100°C for

: 135 :

twem:y four hours. The product after desorbtior. and colu.-n

chromatography over silica gel gave three compounds with -.p.

130°, 163° and 202°C.

^8^17 CoH 8"17

( XCII )

CRH 8" 17

(UIII) (XCIII)

Characterization of the comround, m.p. 130 as 3-oxocholes-

5-en-6-yl chloride ( XCII ) ;

The compound, m.p. 130 was analysed for C^yH_^OCl,

and gave positive Beilstein test. The composition inciccii;

that chlorine was incorporated while three hydrogens and a:

oxygen was lost during the reaction.

: 166 :

Tnis can oe accomodated if we consider epoxide ring

opening with addition of HCl followed by loss of a water

molecule and oxidation by removal of 2H [oxidation of

alcohol to ketone]. This leads to various possibilities

such as XCII , XCIV - .XCVI .

a> Cl

(XCII) (XCIV) (XCV ) (XCVI)


bands at 1710, 16CXD and 800 cm" and indicated the presence

of a nonconjugated carbonyl group, double bond and a carbon

chlorine bond. No other significant band was observed.

The structure (XCIV^ could be discarded on the basis of

i.r. spectrum as carbonyl group present was unconjugated in

nature.

The n.m.r. spectrum showed, complex multiplet centered

at d 2.0, with no clear integration, and methyl protons at

d 1.16, 0.76 and 0.68. The absence of any vinylic proton in

the region d 5-6 easily discarded the possibility of

XCIV - XCVI . This also suggested that the double bona

present [i.r. band l600j was tetra substituted and halogen is

vinylic in nature. These observations go in favour of the

: 187 :

structure (XCII ) vhich can account for the multiplet

centered at d 2.0 as ascribed to the C-2, C-4 and C-7

metnylene protons.

On the basis of above spectral data the compound, m.p.

13C° is characterized as 3-oxocholest-5-en-6-yl chloride

(XCII .). The formation of the compound ( XCII ) can be

explained as first epoxy ring opening by chloride ion,

followed by oxidation of hydroxy group at C-3 (which is

2 30 possible in reaction conditions * ) hydrolysis and then

dehydration as shown in scheme-1,

CgHj_y

Na" Cl~ oxidation

hydrolysis

(XCII)

(Scheme-1)

: 188 :

Identification :;f the compo'jnd with m»p. 163 as 3,6-dJoxo--

5a-cholestane (LXIII) :

>o The compound with m.p. 163^ was analysed for C^^H^.O^

(M ' 400). Compound showed negative Beilstein test.

The i.r. spectrum of the compound showed a band at

1710 cm , the broad signal could suggest the presence of

two carbonyl groups. No other significant band was observec

in the i.r. spectrum.

The n.m.r. spectrum of the compound was also devoid of

any peak in the lower field region. A complex multiplet

centered at d 2.3, observed as methylene envelop could be

assigned to six methylene protons at C-2, C-4 and C-7 which

were a- to carbonyl groups. Other signals were observed at

d 1.1, 0.98, 0.85 and 0.72 for other methyl protons.

By comparison with the authentic sample (m.p., mixed

m.p., and TLC), the compound m.p. 163° was identified as

3,6-dioxo-5a-cholestane (LXIII).

The mechanism of the formation of the product ( LXIII)

from starting compound ( XC ) is suggested as follows

(scheme-2).

: 189 :

C xc )

0-Na

98^17

Na+ cn I Na

^ j j oxidatioji

i-Na

— >

work up

Scheme-2

(LXIII)

Identification of the compound m.D. 202 as 5-hvdroxv-3-oxo-

5a-cnolestan-6»3-vl chloride (XCIII) :

The corr.DOund m.p. 202° was analysed for C27H.tO^Cl,

and snov\ed oositive Beilstein test.


bands at 3390, 1710 and 760 cm" , which were assigned to a

190 :

hydroxyl group, a nonconjugated carbonyl group anc carbo-.-

chlorine bond, respectively. Absence of any band arounc

1600 cm" suggested the absence of carbon-carbon double bond.

The n.m.r. spectrum of the compound showed a r.ultiplet

at d 4.18 integrating for one proton and could be assignee

to equitorial proton at C-6 (Wl/2 = 8Hz). A broadened

singlet at d 3.35 integrating for single proton cojld be

assigned to hydrogen of hydroxy group. A singlet vias observed

at 3.03 for two protons which could be assigned to methylene

protons of C-4 in XCIII , These methylene protons were

adjacent to carbonyl group and other side was flanked by -CH

group. A multiplet at d 2.25 was ascribed to two protons at

C-2. Other signals as singlets were observed at d 1.17, C.53,

0.85, and 0.67 (other methyl protons).

On the basis of above discussion the compound viith n.p.

202 has been identified as 5-hydroxy-3-oxo-5a-cholestan-

6p-yl chloride. The structure was again confirmed zy the

40 mixed m.p. and TLC with the authentic sample

The formation of the compound can be explained as first

the epoxy ring opens up by CI and then oxidation of Z3-

hydroxy group takes place.

: 191 :

Reaction of 3p-hydroxv-5. 6a-epoxv-5g-5-t iqrr.astane (XQ1_J

with NaCl on silica gel ; 3-0xostiqniast-5-en-6-y1 chloride

(XCVIl) 3, 6-dioxo-5a--stiqmastane(XCVIIl) 5-hvdroxv-3-oxo-5g-

stiamastan-6p-yl chloride (XCIX) :

The epoxide (XCI) in absolute methanol was

adsorbed over a powdered mixture of silica gel ana NaCl

(2:1), solvent was evaporated and the dry residue was

heated at 100 C for twenty four hours. The product after

desorbtion and column chromatography over silica gel gave

three compounds with m.p. 289°, 198° an-d 237°C.

^10^21

NaCl

Silica ge !

^10^21

^10^21

(XCVIII) (XCIX)

: 192 :

o Cnarac te r i za t lon of the cn.-ncojnd m.p. 289 as J-oxostiqmast-

5-en-6-yl ch lo r ide (XCVII) :

The compound m.p. 289 was analysed for C^g^^l^'^^ ^^'^

showed positive Beilstein test.

The i.r. spectrum of the compound shovved absorptior.

bands at 1710, 1620 and 800 cm" and suggested the presence

of unconjugated carbonyl group, double bond and a carbon

halogen bond.

In n.m.r. spectrum absence of any peak between d5.C-6.0

showed that no vinylic proton was present, which means tnat

carbon-carbon double bond was tetrasubstituted. A complex

multiplet centered at d 2.05 was observed with no clear

integration and assigned to methylene protons at C-2, C-^

and C-7. Other singlets were observed atiil.18, 1.05, 0.96,

0.78 and 0.65 for other methyl protons.

On the basis of above spectral data and in analogy

with the similar compound obtained ( XCII ) in previous

Case, the compound can best be characterized as 3-oxostig-

mast-5-en-6-yl chloride (XCVII ).

laentification of the compound, m.p. 193° as 3,6-dioxo-5a-

stigmastane (XCVIIIj :

The compound m.p. 198 analysed for C^gH.JD^ and sr.'jwea

: 193 :

negative Beilstein Test. The i.r. spectra-n of the compound

showed a broad band at 1710 cm" , which was assigned to two

caxDonyl groups. Absence of any band above 3000 Cm~

indicated the absence of -OH group and it could be assuTied

that the two oxygen atoms present were in the form of

carbonyl groups.

The n.m.r. spectrum of the compound, m.p. 198 was

also devoid of any significant peak except a multiplet

centered at^2.18, with no clear integration and could be

assigned to methylene protons present at C-2, C-4,and C-7

and a single proton at C-b, All the protons were a- to 2

carbonyl groups. Other singlets were observed at d 1.12,

1.08, 0.97, 0.86 and 0.78 (other methyl protons).

On comparison from the authentic sample by mixed m.p.

and TLC , the structure of the compound was established

as 3,6-dioxo-5a-stigmastane (XCYIIl).The mechanism of the

formation of the compound is given in scheme-2.

Characterization of the compound with m.o. 237° as 5-hvdroxv-

3-oxo-5g-stiqmastan-6^T-yl chloride (XCIX ) :

The compound m.p. 237 , analysed for C^oH.gO CI,

showed positive Beilstein test.


194

bands at 3400, 1715 and 760 cm for a hydroxy group, a

carbonyl group and carbon-chlorine bond.

The n.m.r. spectrum of the compound showed a multiplet

at d 4.2 integrating for one proton with Wl/2 = 9Hz which

could be ascribed to equitorial proton at C-6. A broad

singlet, observed at 6 3.35, also integrating for single

proton was assigned to hydrogen of hydroxy group. Another

singlet was observed at d 3,1, integrating for two orotons

ascribable to methylene protons at C-4 in XCIX . A multi

plet centered at d 2.1 for two protons was assigned to

C2-Hp. Other singlets were observed at d 1.15, 1.08, 0.95,

0.83 and 0.69 (other methyl protons).

On the basis of above discussion and in analogy with

the similar compound (XCIII ; obtained in previous case,

the compound, m.p. 237° can be characterized as 5-hycroxy-

3-oxo-5a-stxgmastan-6^-yl chloride (XCIX) .

experimental

3g-Hvdroxv-5.6a-epoxy-5a-cholestane ( XC ) :

Cholesterol (4 g) in chloroform (35 ml) was treated

with a chloroform solution of perbenzoic acid (1.1 mole)

and kept at 0°C for twenty hours. The mixture was then

wa shed with ice cooled NaHCO-, (55^), water, sodioxthiosul-'3 phate solution and again with water. Removal of the solvent

and crystallization from acetone gave the epoxide (XC)

(2.5 g), m.p. 141° (reported^^, m.p. 142°C).

Reaction of 3S-hydroxv-5.6a-epoxy-5a-cholestane ( XC )

with NaCl on silica oel ; 3-Oxocholest-5-en-6-vl chloride

(XCII ) 3.6-dioxo-5a-cholestane (LXIII). 5-Hvdroxv-3-oxo-

5a-cholestan-66-vl chloride (XCIII) :

The epoxide ( XC ) (500 mg) in absolute methanol

(200 ml) was adsorbed over a powdered mixture of silica gel

and sodium chloride (125 g, 2:1). The solvent was removed

: 196 :

by air drying and the dry residue was heated at 100 C for

twenty four hours. The products were desorbed (ethyl acetate)

and the residue was chromatographed over silica 'gel (20 gm).

Elution with a mixture of petroleum ether — ether (50:1) gave

the compound which was crystallized from methanol to give

XCII , (100 mg)^ m.p. 130°, with positive Beilstein test.

•^ 1710 (C=0), 1600 iC=C), 800 (C-Cl) cm"" .

6 2.0 (mc, 6H, complex multiplet, C2-H2. C4-H2, CZ-H^),



C27H23OCI requires : C, 77.37; H, 10.34%.


gave an oil which was crystallized from methanol to give

LXIII ,(100 mg), m.p. 163° (reported^^, m.p. 168%).

^max. 1^10 (C=0) cm-^.

d 2 . 3 (mc, 7H, complex m u l t i p l e t , C2-H2, C4-H2, C5-H,

C7-H2), 1 . 1 , 0 . 9 8 , 0.S5 and 0.72 ( o t h e r methyl p ro tons )

A n a l y s i s found ; C, 8 0 . 1 ; H, 1 1 . 1

Gdlcd . fo r C27H44O2 • C, 8 0 . 9 4 ; H, 11.07^^.

F u r t h e r e l u t i o n wi th tne same s o l v e n t system ( 1 : 1 ) gave

1?7

ano-her solid which was crystallized from me-;hanol tr affcr::

o 40 '" XCIII (125 mg) m.p. 202 (reported , m.p. 20^:: .

:j5 3390 (OH), 1710 (C=0), 760 (C-Cl) cm"-"-. ^ max.

d 4.18 (IH, m, OH), 3.3b (IH, m, Wl/2 = 8Hz, Cc-pH),

2.25 (2H, m, C4-H2), 1.17, 0.93, 0.85 and O.c" :o-.her

methyl protons).


Calcd. for C27H45O2CI : C, 74.19; H, 10.38%.

3S-Hvdroxv-5,6a-epoxv-5a-stiamastane ( XCI ) :

^-Sitosterol (4 g) in chloroform (35 ml) was treated

witn a chloroform solution of perbenzoic acid (1.1 niole) and

kept at 0°C for twenty hours. The mixture was tnen washed

with water, sodium bicarbonate solution (53 ), water, sodium

thiosulphate solution and again with water. Removal of the

solvent and crystallization from acetone gave the epoxide

( XCI ) (2.2 g), m.p. 138°C .

Reaction of 3g-hydroxv-5.6a-eDoxv-5a-stiqmastane ( XCI)

witn NaCl on silica gel ; 3-Oxostiamast-5-en-6-v: chloride

fXO.-:i) 3. 6-dioxo-5a-stiamastane(XCVIII^5-hvdroxv-3-cxc-5a-

sti:jmastan-6B-vl chloride (XCIX) :

The epoxide (XCI) (5C0 mg) in absolute r.ethinol

: 193 :

(200 mlj was adsorbed over a powdered mixture of silica gel

and sodium chloride (125 g, 2:lj. The solvent was removed

by air drying and the dry residue was heated at 100 C for

twenty four hours. The products were desorbed (ethyl acetate^

and the residue was separated by column chromatography over

silica gel (20 g). Elution with a mixture of petroleum ehter -

ether (50:1) gave the compound(XCVH)which was crystallized

from methanol, (110 mg) m.p. 289°C.

i n, ,, 1'710 (C=0;, 1620 (C=C; and 800 (C-Cl) cm""'-.

d 2.05 (mc, 6H, complex multiplet, C2-H2, C4-H2, C7-H2),

1.18, 1.05, 0.96, 0.78 and 0.65 (other methyl protonsj.


C29H4yOCl requires : C, 77.89; H, 10.59^.

Further elution with petroleum ether - ether (8:1) gave

the compound (XCVIII) which was crystallized from methanol

(120 mg) m.p. 198°C. -

\a.. 1 ^ (C=° ' " •

d 2.18 (mc, 7H, complex multiplet, C2-H2, C4-H2, C5-H,

C7-H2), 1.12, 1.08, 0.97, 0.86 and 0.78 (other methyl

piotons).

Analysis found : c, 81.2; H, 11.2

^9^48^2 ^equi^es : C, 81.24; H, 11.28^.

: 199 :

Elution with same solvent system (1:1) gave the

compound TXCIX) which was crystallized from methanol

(130 mg), m.p. 237 C. Compound showed positive Beilstein

test.

>) ^ 34CXD s(OH), 1715 (C=0), 760 (C-Cl) cm"-'-, max *

d 4.2 (IH, m, OH), 3.28 (IH, m, Wl/2 = 9Hz, C6-3H), 2.1

(2H, m, C4-H2), 1.08, 0.95, 0.83, and 0.69 (other

methyl protons).


^9^49^2^-^ requires : C, 74.88; H, 10.625^.

5feeferentej(

1. G.H. Ott and T. Reichstein, Helv. Chim. Acta., 26,

1799 (1943).

2. L.H. Sarett, J. Am. Chem. Soc, 70, 1454 (1948).

3. H. Reich, F.E. Walker and R.W. Collins, J. Org. Chen.,

16, 1753 (1951).

4. A.H. Soloway, W.J. Considine, D.K. Fukushima and^

T.F. Gallagher, J. Am. Chem. Soc, 76., 2941 (1954).

5. N.S. Leeds, D.K. Fukushima and T.F. Gallagher,

Ibid, It, 2943 (1954).

6. R.J.W. Cremlyn and C.W. Shoppee, J. Chem. Soc, 351b

(1954).

7. Q.R. Peterson and C.T. Chen, J. Am. Chem. Soc, 77,

2557 (1955).

• ^ ^ -L •

8. C.R. Engel, K.F. Jennings and G, Just, Ibid, 73,

6153 (1956).

9. W.R. Biggerstaff and T.F. Gallagher, J. Org. Cher..,

22, 1220 (1957).

10. J. WcKenna and J.K. Norymbersici, J. Cheni. Soc, 2393

(1957).

11. W. Schutt and C. Tanun, Helv. Chim. Acta., £1, 1730 (1958).

12. G.H. Douglas, P.S. Ellington, G.D. Meakins and

R. Swindells, J. Chem. Soc., 1720 (1559).

13. A.T. Rowland and H.R. Nace, J. Am. Chem. Soc, 82,

2833 (1960).

14. C.R. Engel and S.F. Papadopoulos, J. Org. Che.-n., 26.

2868 (1961).

15. H.B. Hanbest, D.N. Jones and G.P. Slater, J. Chen:. Soc,

4472 (1961).

16. T. Nambara and J. Fishman, J. Org. Chem., 22, 21::1

(1962).

17. F. Bernoulli, H. Llnde and K. Weyer, Helv. Chi.T. -.eta.,

45, 240 (1962).

: 202 :

18. W.F. Johns and D.M. Jerina, J. Org. Chem., £8,

2922 (1963).

19. F.C. Chang, Tetrahedron Lett., 22, 2057 (1963).

20. F. Kohen, B.K. Patnaik and R. Stevanson, J. Org. Cher..,

29, 2710 (1964).

21. G.A. Boswell, Ibid, 33(10). 3699 (1968).

22. G.A. Boswell, A.L. Johnson and J.P. McDevitt, Ibid.

36, 575 (1971).

23. B.M. Trost, R.M. Cory, P.H. Schudder and H.B. Neubold,

J. Am. Chem. Soc, 9^, 7813 (1973).

24. G.H. Posner, D.Z. Rogers, CM. Kimzig, G.M. Gurria,

Tetrahedron Lett., 42, 3597 (1975).

25. L.A. Paquette, W.B. Farnham and S.V. Ley, J. Am. Chem.

Soc, 97, 7273 (1975).

26. G.H. Posner and G.M. Gurria, J. Org. Chem., 41, 578

(1978).

27. G.H. Posner, A.W. Runquist and M.J. Chapdelaine,

Ibid, 42, 1202 (1977).

28. G.H. Posner, G.M. Gurria and K.A. Babiak, Ibid, 42,

3173 (1977).

: 203 :

29. E. Keinan and Y. Mazur, Ibid, 43, 1020 (1978).

30. S.S. Nittala and D. Levie, J. Chem. Soc. (Perkin Trans l)

2835 (1982).

31. F.S. Kim, Y.H. Song, B.H. Lee and C.S. Nahn, J. Org.

Chem., 51, 404 (1986).

32. A.R. Suarez and M.R. Mazzieri, Ibid, 52, 1145 (1987).

33. B.D. Corte, J.M. Denis and N.D. Kimpe, Ibid, 52, 1147

(1987).

34. J.T.B. Ferreira, W.O. Cruz, P.C. Vieira and M.

Yanashiro, Ibid, 52, 3698 (1987).

35. T. Nishiguchi, N. Machida and E. Yamamoto, Tetrahedron

Lett., 28, 4565 (1987).

30. Shafiullah, R.K. Singh and R.K. Pathak, J. Indian Chem.

Soc, 64, 192 (1987;.

37. Shafiullah and R.K. Pathak, Ibid, 64, 668 (1987;.

38. L.F. Fieser and M. Fieser, 'Steroids*, Reinhold,

New York, 197 (1959;.

39. I.M. Heilbron, E.R.H. Jones and F.S. Spring, J. Chem.

Soc, 801 (1937;.

40. Ph.D. Thesis of Nadeem Iqbal, A.M.U., 1987.

Cftapter-Jfour

MASS SPECTRAL STUDIES DF STEROIDAL

BENZOTHIAZEPINES

M^tmsim

A survey of literature revealed that no systematic mass

spectral study of steroidal benzothiazepines has been

reported. In the previous chapter we have described the

preparation of a number of steroidal benzothiazepines. These

two events prompted us to examine the mass spectra of several

structurally related steroidal benzothiazepines as an attempt

to establish spectra-structure relationship. The compounds

incluaed in the study are 5a-cholestan[4a,6-bc]-2',3'-dihydrc-

1',5*-benzothiazepine (I), 5a-cholestan[4a,6-bc]-2*,3'-

dihyaro-l',5'-benzothiazepin -3^-yl acetate (ll), 5a-cholestan

[4a,6-bc]-2',3'-dihydro-l',5«~benzothiazepin-3p-yl propionate

(III), 5a-stigmastanL4a,6-bc]-2*,3'-dihydro-l',5'-benzothia-

zepin-3^-yl acetate (IV), 5a-stigmastan[4a,6-bc]-2',3•-dihydro-

l',5'-benzothiazepin-3p-yl propionate (V), 5a-cholestan-

ib,7-bc]-2',3'-cihydro-l',5'-benzothiazepine (VI), 5a-cholestan-

: 2C5

[5, 7-bc j-2' ,3'-dihydro-l' ,5*-benzothiazepin-3p-y.". acetaze

(VII), 5a-cholestan-[5,7-bc]-2',3«-dihydro-l',5'-benzotnia-

zepin-3^-yl chloride (VIII), 5a-stigmastan-[5,7-bc]-2', 3'-

dihydro-1',5'-benzothiazepine (IX), 5a-stigmastan-[5, 7-bc]-

2',3'-dihydro-I',5'-benzothiazepin-3p-yl acetate (X), 5a-

stigmast-3-en[5,7-bc]-2',3'-dihydro-l*,5'-benzothiazepir.e

(Xl), N,S-phenylene-3a-thio-3p-aminocholest-4-ene (XII) and

5oc-cholestan[2a,4a-bc]-2' ,3',4' ,5'-tetrahydro-I* ,5'-ber.zo-

tniazepin-6-one (XIIl).

These compounds are structurally very close to each

other. It was anticipated that they will follow sinilar

fragmentation pattern thus offering a simple and effective

method of their characterization by mass spectrometry. It

is gratifying to note that this indeed seems to be tne case.

The suggested fragmentation pathways get support from

the composition of important ions. However, in the aosence

of mass spectra of appropriate deuterated analogues zr.e

suggested mechanisms of fragmentation remain tentative,

though substituents in some cases compensate this deficiency

to some extent.

: 2C6 :

R

( I )

( I I )

( I I I )

( IV)

(V)

H

AcO

Pro

AcO

Pro

^ 8 ^ 1 7

CgHj^y

^ 8 ^ 1 7

^ 1 0 ^ 2 1

^ 1 0 ^ 2 1

H CQHJ_^

AcO CgHj^y

(VI )

( V I I )

( V I I I ) CI CgHj^-,

( I X ) " ^ 1 0 ^ 2 1

(X) AcO C^QH^^

C10^21 ? 8 ^ 1 7

(XI ) ( X I I ) ( X I I I )

• J S C -

V)

o>

X r i o

O

£7>

+ • Z

o CO

o -o

2 8 2 -

G»72

C7>

CM

62S. 822

0G2

•712'

0 0 2 - CM

€ 9 1 .

6*7l-o

in

o

e » ) -

o i3

- T - —r-o m ;ui 'i^a

: 207 :

In the first series (I-V) only the mass spectrum of

5a-cholestanL4a,6-bc]-2',3'-dihydro-l',5'-benzothiazepine

(I) has been discussed in detail and this may be considerec

as the representative model tor the benzothiazepines (II-V).

The mass spectrum of 5a-cholestan[4a,6-bc]-2',3'-

dihydro-l',5'-benzothiazepine (l) (Fig. 1) gave a very pro

minent molecular ion peak at m/z 491 (C^^^^^l^S). Other

significant ion peaks were observed at m/z 476 (M-CH^), 458

(M-SH), 378 (M-CgHj^^, side chain), 396 (M-95, C^Hj^^), 354

(m/z 476 - C^H^NS), 282 (Cj^gH^gNS), 244 (C^^H^^NS), 243

(C^P,H^_,NS), 230 (C^^H^^NS), 229 (C^^^H^^NS), 228 (C^^H^^NS),

214, 200, 163 (C^H^NS), 149 (CgH^NS), 95 (C^H^^) and lower

mass peaks. The fragmentation leading to the formation of

interesting and important ions have been suggested in the

following schemes.

m/z 476 (M-CH„) :

The fragment ion m/z 476 corresponds to the loss of a

methyl group from the molecular ion.

m/z 458 [M" '- 33(SH)1 :

This fragment ion corresponds to the loss of mass unit

: 2:8 :

33, which is best regarded as the loss of SH from molecular

ion. The loss of SH may occur in two phases i.e. firs*, the

loss of hydrogen occurs from the molecular ion as is evidenced

by the presence of fragment ion peak m/z 490 (Scheme-1).

Scheme-1

^8^17

-H.

M. 491 ( ! • ) m/z 490

Subsequen t ly t h e l o s s of s u l f u r occur s t o g ive the

ion m/z 458 .

C Q H - I 8"17

+so>_/

m/z 490

e t c

m/z 458 (la)

: 209 :

Alternatively the fragment ion m/z 458 can be shown to

arise from the molecular ion as in the following Scheme-2.

Scheme-2

^8^17

o etc

( ' m/z 458 (la)

It may be pointed out that ion peaks both at m/z 490

and 458 are very weak.

m/z 396 [M"^' - 95l :

The fragment ion m/z 396 corresponds to the loss of

mass unit 95 which may involve the loss of ring 'A* and

angular methyl group at C^Q according to Scheme-3.

Scheme-3 : 210 :

^8^17

Mt 491 (I") m/z 396 (lb)

The fragment ion peak at m/z 396 is very weak. It is

expected to be so in view of the ion structure (lb) having

two four membered, strained rings.

m/z 378 [M"^'- CgHj^^, side chain] (C^^H^^NS) :

The loss of side chain is of regular occurrence in the

mass spectra of steroidal compounds. In the present case

two modes can be suggested.

A. Hydrocarbon direct fragmentation :

Scheme-4 CgHj_7

H ^ 8 ^ 1 7

nrtS ^

( I ' " ) M+-491

( i ;

: 211 :

s' i?

-CgH-|_y

m/z 378 (Ic)

B. Fragmentation due to hetero atom :

Scheme-5

CsHi?

Mt (I")

^8^17

< > etc,

m/z 378 (I c'j

: 212

This scheme can also be rewritten in a concerted manner,

^8^17

<i—> etc

il") m/z 378 ( I c ' )

m/z 354 (m/z 476-2-aminothiophenol moiety) ;

The loss of 2-aniinothiophenoi moiety can be shown

accoxding to scheme-6.

Scheme-6

^8^17

-CHr

>•'•' ( ! ' • ;

m/z 476

; 213 :

^ ->

n/z 354 (Id)

m /z 282 (C^QH2ONS) :

The formation of this ion m/z 282 can be shown according

to scheme-7, but the ion corresponding to the loss of mass

unit 140 (i.e. m/z 351) is not discernible. It was expected

that the ion m/z 351 should have been formed.

CgH-|_7 Scheme-7

-CgH^^CH^CH^

( I " * ; m/z 351

: 214 :

< >

S N

H (le) m/z 282 (le')

In view of the absence of ion peak at m/z 351 an

alternative scheme-8 for the formation of m/z 282 is being

proposed,

Scheme-8 ^8^17

^8^17

(I'") CgHj_7

S "l

// W

< > etc

m/z 2S2 (le)

: 215 :

m/z 244 and 243 :

Perhaps the most significant ion peak in the spectrum

is m/z 243. Its formation can be shown to occur in more

than one way. One of the possibilities is the involvement

of the ion m/z 244 (a small peak) which on one hydrogen

loss can give rise to the ion m/z 243 (Scheme-9).

Scheme-9

C8Hl7

(I")

m/z 244 (If)

-H

m/z 243 (ig)

: 216 ;

The proposed structure for the ion m/z 243 agrees witr.

the composition C,(-H,yNS. However, it appears doubtful that

such a strained structure having a cyclobutane moiety will

have stability enough to be accumulated to attain such a high

(,%) relative abundance. In view of the apparent importance

of the ion m/z 243 it was considered desirable to suggest an

alternative pathway for its formation. Such an attempt has

been made in Scheme-10.

98Hl7

Scheme-10

H

(!•)

dg')

H-S+ -N:

m/z 243 dg" )

etc

: 217 :

m/z 230. 229 and 228 :

These important ions m/z 230, 229 and 228 can be shown

to arise according to scheme-11. These ions along with the

ion m/z 243 are of diagnostic value for [4a,6-bc] benzothia-

zepines (l-V) derivatives. They are not observed in similar

compounds (VI-XIl) involving 5,7-benzothiazepine steroidal

derivatives,

Scheme-11 98^17

i/z 230 (Ih)

m/z 22 9 di')

: 213 :

Alternatively the ion m/z 229 can be shown to arise

without the involvement of ion m/z 230.

m/z 229 (li')

The ion m/z 228 may result by the loss of one hydrogen

from the ion m/z 229.

Scheme-12

H H

m/z 228 (Ij) m/z 229 (li') m /z 223 dj')

I \\\

m /z 229 (lij m/z 228 (Ij ' • ;

: 219 :

m/z 163 :

The presence of nitrogen and sulfur in the ion m/z 163

clearly indicates that the steroid rra~e work is lost in a

manner that three carbons i.e. C4-C6 re.-.ain v ith the frag

ment ion. This ion m/z 163 may be arising according to

fragmentation proposed in scheme-I3 ar.c according to this

scheme it can also be taken as a characteristic fragmentation,

Scheme-13

(I")

->

<r etc

m /2 163 (Ik)

: 220 :

m/z 149 (CgH^NS) :

The fragment ion peak m/z 149 corresponds to the loss

of CH^ from fragment ion peak m/z 163 (Ik). It may be pointed

out that the ion peak m/z 149 is quite a strong peak which

can be explained because of the formation of a stable six

membered ring.

Scheme-14

•> S >f/-H etc

(Ik) m/z 163 m/z 149 (II)

m/z 95 (CyHj j ) :

This fragment ion may occur as shown in scheme-15.

Scheme-15

^8^17

m/z 95 (Im)

(I")

- o o

-J -

•7es -

o o o

jui ' laa

: 221 :

Ring 'A' derivatives as (.LI —• V) behave quite

similar to the parent benzothiazepine (l) ' .

The mass spectrum of 5a-cholestan[4a,6-bc]-2',3'-

dihyciro-l',5'-benzothiazepin-3^-yl acetate (II) (Fig. 2)

gives prominent molecular ion peak at m/z 549 (C2P^H^202^^ *

Some significant corresponding peaks obtained are m/z 534

(M-15), 507 (M"^H2=C=0, (42)), 489 (A^-CH3C00H). Other

significant ion peaks corresponding to I are obtained at

m/z 474 (m/z 489-CH3), 456 (m/z 489-SH), 436 (M" * - side

cnain, CgH,^), 396 (m/z 489-93), 352 (m/z 474 - 2-aminothio-

pnenol moiety), 280 (Cj gHj gNS), 242 (Cj 5Hj .NS), 241

(CJ^^H^^NS), 228 (C^^K^^NS), 227, 226 (C^^Hj^^^S), 212 (m/z

228 - CH3), 198, 163, 149, 93 and lower mass peaks.

m/z 507 ;

The ion m/z 507 corresponds to the loss of ketene

(CH2=C=0) from the molecular ion. The peak is common in

all acetate derivatives and may be shown according to

scheme-16.

Scheme-16

: 222 :

(II) (II'} m/z 507 (Ila)

m/z 490 :

The ion m/z 490 corresponds to the loss of acetate

moiety from the molecular ion.

-1 -*

(ID m/z 49.0 (lib) (lib')

- o o

to

9»iS o

- m

IZS

U O T

9S '7 -

' ^ * ' i « i i i -6Qn

• ) / •? '

Rq«7

O S « J -

o - o in

o ^3 96C

9ZC

2SE=VS

- o - o n

8 2 2 - ^

€91 — 6«)l- -8

o o

—I—

-

1 o

1 m CM

M - ^ ^ , , ^ ^ 6

o - o

: 223 :

m /z 489 :

The ion m/z 489 corresponds to the loss of acetic

acid from the molecular ion .

H,(r<=-P-N

CsHi" •

( I I ) m/z 489 (lie)

The mass spectra of 5a-cholestanL4a,6-bcJ-2*,3'-

dihydro-l',5'-benzothiazepin-3^-yl propionate (III) (Fig. 3)

gives prominent molecular ion peak m/z 563 (C- Hc 202NS )

along with other significant ion peaks at m/z 548 (.M-CH ),

521 (M"*"* - 42, CH2=C=0), 491 (M"^* - 72, CH2CH2CO2), 490

(M^* - 73, CH3CH2CO2), 489 (M'-74, CH^CH^COOH) , 474 (m/z

489-CH3), 458, 456 (m/z 489 - SH), 450 (M"^- side chain,

CQHJ^^), 396 (m/z 489 - 93), 378 (m/z 491 - side chainj, 376

(m/z 489 - side chain), 352 (m/z 474 - 2-aminothiophenol

moiety), 280 (C^yH^gNSj, 242 (Cj^^H^^NS;, 241 (C^^H^^NS), 223

^^14^14^^^' 227, 226 (C^^H^^m), 214, 212 im/z 228 - CHJ,

200, 198, 163, 149, 93 and lower mass peaks.

: 224

-CH^

m/z 534 <"

-CH3COOH AcO

m/z 474

side chain •—> m/z 476

I-CH3COOH

m/z 376

m/z 352

M" 549 (C3 Hpjj 02NS;

(III'

m/z 4 56 <-

m/z 396

m/z 280 (C^gH^gNs)

m/z 149 (CgHyNS)

f

m/z 489 (C^^H^^NS)

m/z 242 " / 22

/z 163 (C9H9KS)

m/z 93 (C7H9)

/z 228 (Cj Hj NS)

-CH,

Nl'

m/z 241 m/z 226

(Cj^4Hi2NS)

m/z 212 (C13H11NS;

: 225 :

m/z 548 ^ -CH3

Pro

-C^H^COrJri

m/z 474

-C^H4NS

m/z 352 '

m /z 489 ^ -SH

m/z 396

m/z 280

-side chain > m/z ^50

-C2H5COOH

^

m /z 378

M^ 563 (C3^H^3 02NS)

i^r^ -92 S

m/z 149

(CgHgNS)

r

m/z 489 (C-_H^_NS) 33 47

» m/z 163 (C9H9NS)

m/z 93 (C7H9)

^ m/z 228 (C H NS) 14 14

m/z 242

m/z 241

m/z 227 (C^4H^3NS)

m/z 226

^^14^12^^^

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: 226 :

The mass spectrum of 5a-stigmastan[4a,6-bc]-2',3'-

dihydro-l',5'-benzothiazepin-3^-yl acetate (IV) (Fig. 4)

gives prominent molecular ion peak at m/z 577 (C2-7Hp p 02NS)

along with other significant ion peaks at m/z 562 (M '-CH^),

535 (M"^*-CH2=C=0), 518 (M"^' - side chain), 436 (m/z 562 -

2-aminothiophenol moiety), 382, 296, 295 (296-H), 228

(Cj gHj gNS), 248 (280-S), 242 {C^^H^^NS), 241 (Cj^^H^^^NS), 228

(Cj^^Hj^^NS), 226 (Cj Hj ^ S), 214, 212 (228 - (H+CH3)), 190,

136, 125 and other lower mass peaks.

Mass spectrum of 5a-stigmastan[4a,6-bc]-2*,3'-dihydro-

1*,5'-benzothiazepin-3p-yl propionate (V) (Fig. 5) gives

prominent molecular ion peak at m/z 591 (0^0^=702^^^ along

with some other significant ion peaks at 576 (M * - CH^),

549 (M'^*-CH2=C=0), 535 (M"*'*-CH2CH2C0) , 518 (M"^*-CH3CH2C02),

517 (M"^*-C2H^C00H), 502 (m/z 5I7-CH3), 486 (wT-105), 484

(m/z 517-SH), 450 (M"*"* - side chain), 376 (m/z 517 - side

chain), 380 (m/z 502 - 2-aminothiophenol moiety), 354, 296,

295 (m/z 296-H), 280 (C^gH^gNS), 242 (Cj^^H^^NS), 241

(C^^Hj^^NS), 228 (C^^Hj^^NS), 214, 212 (m/z 228 -H-CH3), 200

198 and other lower mass peaks.

: 227

m/z 562 < - side chain

> m/z 436

-CH.

m/z 421 m/z 535 -CH3COOH Mt 577 (C37H55O2NS;

m/z 502

-CH,

m/z 280 ^ (CIQHIQNS)

m/z 24^ (C15H16NS;

m/z 2 4 1

m/z 248

($8 " l 8 ^ ' ^

( I V )

-CH3COOH

^

- j + m/z 149 (CgH^NS)

910^21 ^

_> m/z 163 (C9H9NS)

m/z 517(C3P,H5^NS)

W z 93 (C7H9)

m/z 223 " ^ " 3 (C H, NS; ^ w z 212

' ' 14

m/z 227 ^ 14-^13 ^ s ;

i m/z 226

(C14H12NS;

: 225 :

$> m/z ^z -."

^

-C-H=;CCQH

m/z 549

-C2H^CC2 j /2 37-

\ m/z 518

m/z 591 (C38H57O2NS)

'-side cnam

-CH-

m )/z 502 <-

^C2"5^°2" /""

'6^4'^^m/z 517 m/z 380 (C3P,Hpjj NS)

m/z 280 (C^gH^gNS)

m/z 225 C:-j_ Hj 4\'S;

m/z 242 (c^^H^^Ns;

V -., z 212

-H

m/z 241

^ 15 15 ''"''

: 229 :

A comparison of these spectra of five benzothiazepines

(Fig. 1-5) clearly sho'.ved remarkable sirr.ilarly between them.

The presence of different substituents in different parts of

the five benzothiazepines structure (I-V) help in better

interpretations of their mass spectra.

A screening of these spectra revealed that these

steroidal benzothiazepines undergo characteristic fragmenta

tion which can be exploited for identification purpose. For

the present we represent two cleavage modes as shown in thp

structure below: 5,

Cleavage mode a-a' provides a prominent ion peak at

m/z 243 (C^^H_^7NSj in the structure of I (Fig. 1). Analogous

peak at m/z 241 (C^^H^^NS) after the expulsion of acetic

acid and propionic acid can be seen in tne mass spectra of

(ll-y) (Fig. 2-b}. The presence of C^QH^^ side chain in

n

E6*j.

•iz*?-9 Z n „

fiO«7

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230 :

(IV; and (V) does not make any difference (regarding rhe

fragment ion peak at m/z 241) and this supoorting the

fragmentation of a-a' cleavage mode.

The cleavage mode b-b* is reflected into ion pea.<s at

m/z 282 in I and at m/z 280 in the remaining four mass

spectra.

In continuation with the study of benzothiazepines we

carried out the stuay of mass spectra of benzothiazepines

(VI-XI) derived from 5-en-7-one derivatives. Here we are

discussing the mass peaks of the compound 5a-cholestan

L5,7-bc]-2',3'-dihyGro-l',5'-benzothiazepine (VI).

The mass spectrum of 5a-cholestan[5,7-bc]-2',3'-dihydro-

1',5'-benzothiazepine (VI) (Fig. 6) gives a very prominent

molecular ion peak at m/z 491 (C^oH.pI^S) which is the base

peak also. Other significant ion peaks are observed at m/z

476 (M'^*-CH3), 475 (M"^*-NH2 °^ "" ^ 476-H), 406 {it'-C^r-^^),

378 (M" ' - side chain, CgH^^), 296 (Cj^pH22NS), 283 (C^^H^^NS),

282 (C^gH^oNS). 281 (C^gH^^NS), 270 {C^^H^^KS), 268(C^7H^gNS),

267 (Cj^^H^^NS), 255[CC^^H^7NS), {C^^H^^)] 243 iC^^H^ySS),

240 (m/z 255-CH3), 228 (m/z 243-CH3), 225 (m/z 24O-CH3), 212,

198, 163, 149 and otner lower mass peaks.

The formation of some of the significant fragment ions

nave been rationalized in the following schemes.

: 231 :

m/z 476 :

The fragment ion m/z 476 is due to the loss of a methyl

group from the molecular ion.

m/z 475 :

The ion m/z 475, corresponding to the loss of 16 dalton,

may be due to the loss of NH2, from the molecular ion or from

the loss of hydrogen from the fragment ion m/z 476. The loss

of NH^ though not so common can be shown to arise according

to Scheme-17.

C8H17

(VI') ^8^17

Scheme-17 (^8^17

CgH-,_y

: 232

V f

^8^17

s >

m/i

T

: 475

, 9 8 " l 7

+

iVlb)

The loss of hydrogen from the fragment ion m/z 476 can

occur in different modes some of them are shown in scheme-i8.

Scheme-18

m/z 476 (Via)

(Vie;

; 233 ;

m /z 476 (Via')

( ^ ••' c„H,r

m/z 406 : m /z 475 (VIC")

8"17'

The ion m/z 406 corresponds to the loss of mass unit

85 (C.H,„) from the molecular ion which may be derived from

the side chain. The loss of C,H,_ from the side chain is O lo

not a matter of regular observation.

m / z 378 :

The loss ot sice chain (CpH,-,) is of regular occurrence

in the mass spectra of corresponding cholestane series.

:234:

which can be shown by two different mechanisms according to

schemes ~ 19 and 20.

Scheme-19

98^17

• >

(VI) ( V I " )

^8^17

C^ S N

// w

m / z 378 (VId)

: 23b :

CoH 8"17

( V I ' )

< >

m/z 378 (VId«)

^ 8 ^ 1 7

<; > e t c .

< >

: 236 :

Several fragment ion peaks such as m/z 296, 283, 270 and

2 43 are analogous to the corresponding ions derived from 5

cholest-5-en-7-one (XIV) under electron impact .

Scheme-21

m/z 189

CQH^JI •

m/z 136

m/z 176 m/z 163

m/z 296 and m/z 281 :

The ion peak at m/z 296 (Cj^^H22NS) may be formed by the ]oss

of side chain, ring D and part of ring 'C* in the followinc

manner.

: 237 :

^ 8 ^ 1 7

( V I ' ) CoH 8 " 17 ^ 8 ^ 1 7

^ 8 ^ 1 7

^

^

->

m/z 296 ( V l f ) m/z 281

: 238 :

m/z 283 and m/z 268 :

The ion m/z 283 (C,gH ,NS) may form from the ion (Vie')

which easily losses a methyl radical giving rise the fragment

ion m/z 268.

CgH^y Scheme-23

> -tu-• >

+N-H

(Vie*) m, /z 283 (VIg)

+N-H +N-H

(Vlh) m/z 268

m/z 282 and m/z 267 :

(Vlh')

The formation of this ion peak can be shown as given in

the scheme-24, and m/z 267 by the loss of CH^ from ion peak

m/z 282.

Scheme-24

: 239 :

CEiHl?

(VI")

-CH.

- -C5"8 • >

m /z 267 (VIj) (VIj') m /z 282 (VIi)

m/z 270 and m/z 255 :

This ion m/z 270 corresponds to the composition

C,yH ^NS and its formation can be shown from the ion (Vie)

ds outlined in scheme-25 and m/z 255 occurs due to the loss

of methyl group from the ion m/z 270.

Scheme-25

: 24C

(Vie)

->

m, /z 270 (VIk)

-CH,

+N—H

(VII)

<: > etc

H

(vir)

rr./z 270. m/z 243 and m/z 228 :

This ion peak m/z 243 (C,p-H,yNS) may arise from ion

(vie ) in the following manner and m/z 228 from the m/z 243

by the loss of CK^.

: 241

Scheme-26

CsHiy

(Vie) ^8^17

^

->

CoH 8" 17

^8^17

m/z 243 (Vim)

-CH,

\\\ m/z 228 N+

m/z 255. m/z 240 and m/z.225 : ""/" 70 (VIk')

The ion peak at m/z 255 may arise from the fragment

ion m/z 378 (Via') by the loss of 2-aminothiophenol moiety

(C H_ NS) according to the scheme-27. The fragmentation peak

: 242

at m/z 240 arises by the loss of a methyl radical from

m/z 255 while m/z 225 arises from the loss cf two metnyl

racicals.

Scheme-27

(VIn; m/z 255 (Vin')

-CH3

m/z 2^0 (Vlo)

4 7- etc

m/z 225 (VIpj

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The mass spectrum of 5Q:-cholestan[5, 7-bc]-2', 3 '-

dihydro-l',5'-benzothiazepin-3p-yl acetate (VIl) (Fig. 7'

gives a very prominent molecular ion peak at m/z 5-5

{C^Jit^P2^S ) ; otner significant ion peaks are observec az

m/z 548 (M'^'-H), 490 {M*''-CH^COO) , 489 {M^'-CH^COOK,, 4£3

(m/z 489-H}, 474 (m/z 489-CH3), ""^ ^^^^ 474-H), 45c (u/z

488-SH), 436 (M"^'- side chain), 427 (M"*"*-C^H^NS) , 421 (r./z

436-CH3), 412 (m/z 427-CH3), 409 (M"^--CH2=CHCgH^-,), 4C3

(M"*"*-CH2CH2CgH^y), 404 (m/z 436-S), 403 (m/z 436-SH;, 367

(m/z 427-CH3COOH;, 281 (Cj gHj gNS), 268 (m/z 281 - CH3}, 267

(C^jH^^m), 266 (m/z 267-H), 241 (Cj H p NS), 200, 157, I75,

160, 151, 148 and other lower mass peaks.

The mass spectrum of 5a-cholestan[5,7-bc]-2',3'-Gihydrc-

1', 5*-benzothiazepin-3f3-yl chloride (VIII) (Fig. 8/ gives a

very prominent molecular ion peak at m/z 527/525 (C-^H.-'JSCl),

other significant ion peaks are observed at m/z 512,510

(M"^*-CH3), 492/490 (M'^'-SH), 491/489 (m/z 492/490-H\ 490

(M"^--C1), 489 (M'^--HC1)*^, 474 (m/z 409-CH3), 405/4C3 (M""--

C^H^NS), 404/402 (m/z 405/403 - H), 389/387 (m/z 4C-i/<32 -

CH3), 387/385 (M'^*-CgH^^CH=CH2), 382 (M"^*- side chain ^ 2CHj,

376 (m/z 489-C^Hj^^, side chain), 367 (m/z 404/402 - Zl) , 3ct

(m/z 4O4/402 - HCl), 365 (m/z 366-H), 350 (m/z 365-^.4-), 33c,

324, 319/317 (C^gH^^NSCl), 295 (C^^H^^NS), 292/290 ,-n, z 405

403 - side chain;, 281 (C^gH^^NS), 268 (C^^^H^gNS;, :52(C^^H.4

NS), 241 (C^^H^^NS), 227, 213, 210, 201, 200, 1^6, 172, 187

185, 175, 172, 161, 158, 156, 135 and other lower rass c-dks.

: 244 :

m/z 548 <•

— oHo—CH—CpH] "7

m/z 409

-CH2CH2C8H17

m/z 408

98^171 *

Mt 549(VIl)(C3^H^j^02NS)

-CH^COo\^-C.H NS 3 \ o 4

m/z 403

C8H17 .1

m/z 427

-CH'

-CH3COOH

^

m/z 412 m/z 367

-H

m/z 488

-SH

/

^ m/z 489

CH3

m/z 474 \v / ^ -7 m/z"" 281 , ^/^ 267

(C_H_NS) (C;L7"^7NS)

'-H

"^ m/z 241 (Cj Hj P NS)

18 19 -H

m/z 473 -CH. ^

\y m /z 266 (Cj^yH^^NS)

m/z 206 (Cj yHj NS)

: 245 :

m/z 512/510 <

- /CH2=CHC8Hi7

m/z 387/385 -C8H17+2CH3

> m/z 492/490

m/z 292/290

j-side chain

%/z 405/403

m/z 382

m /z 474 "^

m, /z 376

m/z 295

m/z 319/317 {C^QH^QHSCD

/z 350

m/z 241

m /z 281 m/z 266

(C^gH^^NS)

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: 246 ;

The mai.s spectrum of 5a-stigma5tan[5,7-bc J-2', 3'-

dihydro-l',5'-ben20thiazepine (IX) (Fig. 9) gives a very-

prominent molecular ion peak at m/z 519 (C2^H^2^1S), Other

significant ion peaks are observed at m/z 504 (M * - CH^J,

503 {W.'^'-NH^), 476 (M'*"*-43, trom side chain), 434 (MI-SS,

trom side chain ), 378 (M * - side chain, CJ^QH2J^), 295

iC^gH^^NS), 283 (Cj_gH2j_NS;, 282 (C^QH^QriS), 280 (C^gHj^gNS),

270 CCJ^7H2QNS;, 268 (C_^7H^gNS), 255 (.Cj Hj NS;, 243

(C^^Hj^^NS), 228 (243-CH3), 254 (378-C^H^NS), 239 (254-CH3),

224 (239-CH3), 212, 198 and other lower mass peaks.

The mass spectrum of 5a-stigmastan[5,7-bc]-2*,3*-

dihydro-1',5*-benzothiazepin-3^-yl acetate (X) gives a very

prominent molecular ion peak at m/z 577 (CoyHf,-o^Ns) • Other

significant ion peaks are observed at m/z 576 (M''"*-H), 535

(M'*'*-CH2C0), 518 (M'^*-CH3C00), 517 (M"*" *-CH3COCH), 484 (m/z

517-SH}, 502 (m/z 517-CH3), 455 (M'^^'-C^H^NS), 440 (m/z 455-

CH3), 436 (M" ' - side chain}, 421 (m/z 436-CH3}, ' ^ ^^^' ~

CH2=CH-CJ^QH2^), 408 (M""' - CH2CH2CJ^QH23^), 404 (m/z 436-S),

403 (m/z 436-SH), 395 (m/z 455-CH3COOH), 281 (^.^gH^gNS), 276

(m/z 28I-CH3), 267 (C^^H^^NS), 266 (m/z 267-H}, 241 (C^^H^^MS)

200, 197, 175 and other lower mass peaks.

: 247 :

m /z 518

-H

m/z 503 <--NH^

m/z 504

m/z 283 (C^QH^-^NS

~CH'

m/z 268

^ ^^ mil. 295

^10^2

4-m/z 280

(C^gH^gNS)

.T m/z 476

'rom side chain

-85 from side cT ain '"/ ^^

-side chain

M. 519 (IX)

C35H53NS)

2 «

" 2 1 ^ 1 0 \ f"/z 243

/z 351 15^17'

-CH,

m/z 378

m/z 254(C^9H2^)

-CH,

m/z 239

I-C5H9

I -CH3 m/z 228 ,

m/z 270 tCj^^H^^NS;

(C;L7H2ONS)

-CH, m/z 282 (C^8H20^S)

-CH,

m/z 267 (C _,H NSJ

-CH-

m/z 255

(C;L6HI7NS>)

: 248 :

m /z 421

/S -CH,

-side chain > m/z 436

-S

— CH2=CH-C J^QH^ j

'"/^ " " " - C H ^ C H ^ C ^ Q H ^ M ! 577 (X)

(C37H55O2NS)

m/z 408 -CH3CCX)

m/z 518

m/z 455

-CH2CO

m/z 535

m/z 404

i -m/z 4C3

m/z 484

m/z 502

m/z 517 (C H ,NS) 35 5i

m/z 281

(C^gH.^NS)

•CHQ I m /z 276

m/z 241

m /z 267

(C^^H^^NS)

-H

m/z 266

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: 249 :

m/z 516 m/z 476

m/z 502 <--CH3

m/z 501

m/z 281 (C^gH^^NS)

CH,

-Mt- 517(XI) CC35"57^SJ

m/z 376

m/z 252

m/z^ 24/''l9''f ^ m/z 268 (Cj^p^H^^NS) |-^":

(c'^^H^^NS) '"/ 349 (C^^HJ^QNS) ^ ^/X 237

m/z 266 (C17H16NS;

-CH V-CH.

m/z 278

"^5^9 ,

V m/z 280

-CH-

m/z 226m/z 222

m/z 253 ^^14^12^^

(C^^H^^NS)

-CH-

V m/z 265

(Cj yHj p NS)

J -

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9Z«7' e 9 « ] _

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: 2b0 :

The mass spectrum of 5a-stigmast-3-en-[5,7-bc,-2', 3'-

dihydro-l',5'-benzothiazepine (XI) (Fig. 11) gives a very

pro.iinent molecular ion peak at m/z 517 iC^^^î^^^' Other

significant ion peaks are observed at m/z 516 (M-H), 502

(M'^--CH3), 501 (M"'--NH2), 474 (M"^-43). 430 {M^'-Bo), 378

(M-'--CôH2i). 293 (C^^^H^^NS), 281 (C^gH^^NS), 280 (C^gH^gNS),

278 (C^gH^^NS), 268 (C^-^H^gNS), 266 (C^^H^^NS), 253

(C^^H^^NS), 241 (C^î^NS), 226 (24I-CH3), 252 (376-C^H^NS),

237 (252-CH3), 222 (237-CH3), 210, 196 and other lower mass

peaks.

The mass spectrum of N,S-phenylene-3a-thio-3^-amino-

cholest-4-ene (XII) (Fig. 12) gives a very prominent mole

cular ion peak at m/z 491 (C33H^gNS) (87.5?^). Other

significant ion peaks are observed at m/z 490 (M *-H), 476

(M^*-CH3), 459 (M'^'-S), 458 (M'*"*-SH), 378 (M"^*- side chain),

243 (CJL^HJ^^NS), 242 (C- p Hj NS), 228 (C^^Hj^^NS), 227 (m/z 242-

CH3), 214 (m/z 228-CH3), 163 (C^H^NS), 162 (C^HgNS) (base

peak J,149 (m/z 163 - CH^)t 136 and lower ion mass peaks.

Some mass ion peaks are similar as in the benzothia-

zepines discussed before so they have not been discussed in

detail for example, m/z 490 (M"*'*-H), 476 (M'^*-CH3), 459

(M+--S), 458 {M'^'-SH), and 378 (W"*"* - side chain, C^H^j).

m/z 243. 242. 228 and 227 :

The ion m/z 243 and 242 arise due to the loss of side

: 251 :

chain ring D, C and part of ring B as shc/.n in the follov.'ing

scheme-28, while m/z 228 and 227 arises from the loss of

methyl group from the ion m/z 243 and 2^2 respectively.

Scheme-28

^8^17

(XII')

m/z 243 (Xlla) -CHT

m/z 228 (XIIc)

(Xllb;

m/z 227 (Xlld)

; 2o2

Ion peak m/z 228 also arises from the molecular ion (XII'

in the following manner.

(XII';

Schenie-29

^8^17 ^8^17

m /z 229 (Xlle) m /z 228 (XIIc')

m/z lt>2 :

The fragment ion m/z 162 constitutes the base peak

(lOO%) of the spectrum and its formation can be rationalized

according to scheme-30. From the molecular composition

(C^HgNS) it appears that the ion consists of aminothioDher.-l

moiety and three other carbon atoms.

Schene-30

: 253

(xii;

^8^17

(XII' •)

< ->

m/z 162 (Xllf)

> etc.

m/z 149 :

The fragment ion m/z 149 (CgH-,NS) arises froi the

molecular ion (XII'M in the following manner (Scr.e7ie-3:)

Scheme-31

(XII")

: 2D4 :

• < >

m/z 149 CXIIgj

m/z 136 :

+

H

The fragment ion m/z 136 (CyH^NS) also arises from the

molecular ion (XII''^ as shown in scheme-32.

ScheTie-32

( X I I ' •)

^8^17

->

m/z 136 (X l lh )

<-

H

& : > '

A

y

e t c

o in

? ^ •

o m

8QS

9 0 S 26«7—J

6 9 •) 6Z*j

•79+J-l

o - i n

J-

ie*7

oon-2BC_ oee

Z82

093 6S2'

o o in

J -

S»J2

912 812

•J02

291-

681-

szi-£91 ^'JL

6*)l'

o m

o o

o

o -o

CVJ

s

o - o

. o m

I — o o

- T — ID

—T" O in

- X -m CM

•»U| ' I 'M

: 255 :

The mass spectrum of 5a-cholestan-L2a,4a-bc]-2•,3',4',

5'-tetrahydro-l*,5'-benzothiazepin-6-one (XIII) (Fig. 13)

gives a very prominent ion peak at m/z 507 (C^^H^nONS) (1C0%)

Other significant ion peaks are observed at m/z 506 (M '-H),

492 (M'^*-CH3;, 489 (M'*'*-H20;, 479 (M'*'*-C0), 464 (m/z 479-CH3),

431 (m/z 464-SH), 394 (W*- side chain, CgK^y), 379 (m/z 394-

CH3), 247 (C^QH^^), 246 (C^^H^^ONS), 245 (Cj^^H^^ONS), 231

(m/z 246-CH3), 230 (m/z 245-CH3;, 218 (C^3Hj^^NS), 217 (m/z

246-CO;, 216 (m/z 245-CO), 205 (Cj j j ONS , m/z 23I-C2H2),

204 (Cj j Hj ONS, m/z 23O-C2H2), 162 (C^HgNS), 149 (CQH-,NS; and

lower mass peaks. Some significant peaks are discussed below

in detail.

m/z 247 :

The ion peak m/z 247 arises by the loss of ring A and

B with benzothiazepine moiety from the molecular ion and may

be shown in the following manner (scheme-33).

Scheme-33

CgHj_y CgHj_y

i^lll) (XIll')

; 256 :

^8^17

m /z 247 (Xllla)

-> etc

m/z 246 and m/z 218 :

The ion peak m/z 246 arises from the molecular ion

(XIII* •) by the loss of the side chain, ring D, ring C and

part of ring B in the following manner Cscheme-34) and m/z

218 arises from the loss of C0(28) from the ion m/z 246

(Xlllb).

Scheme-34

^8^17

(XIII'')

-CO S""'

H

W // I H

m/z 246 (Klllb) m/z 218 (XIIIc)

257 :

m /z 245. m/z 217 and m/z 216 :

The ion m/z 245 (C,^H.ppNS) arises from the ir,oleculai

ion (XIII'') as shown in scheme-35 and m/z 217 arises by tr.e

loss of CO from the fragment ion m/z 245, while m/z 216

arises by the loss of a hydrogen from the ion m/z 217 (Xlllf)

C„H Scheme-35

8"17

(XIII'•)

m/z 245(XIIId)

m/z 230 (Xllle)

m/z 217 (Xlllf) m/z 216 (XII ig)

: 258 :

m/z 231, m/z 230. m/z 205 and m/z 204 :

The ion peak m/z 231 may be shown to arise due to the

loss of CHo radical from the ion m/z 246, which apoears to

loose a hydrogen to give rise to the ion m/z 230, while

m/z 205 and m/z 204 arise by the loss of acetylene from the

ion m/z 231 and m/z 230 respectively.

Scheme-36

m/z 205 (XIIIj) m/z 204 (XIII k)

m /z 218 :

The ion peak m/z 218 arises by the loss of side chain,

ring D, ring C and ring B as shown in scheme-37.

Scheme-37

: 2o9 :

^8^17

(XIII'") 98^17 8 '17

"'/ 62 : ^1^ 218 (XIIIl)

The ion m/z 162 may arise according to fragmentation

pattern proposed in scheme-38 and according to scheme it

can also be taken as a characteristic fragmentation. This

peak (83.3^) is the second strongest after the molecular ion

peak (wnich is the base peak) and the ion is highly stablized

by resonance explaining the abundance of the peak.

: 260 :

(XIII"')

m/z 162 (XXXm)

Scheme-38

^8^17

->

etc

m/z 149 :

This ion peak m/z 149 (CgH^NS) (50%) (XIIIj) also

arises from the molecular ion (XIII'*') in the manner shown

in scneme-39. This peak is also quite a strong peak and its

structure also seems to be resonance dependent.

Scheme-39

H

(XIII' ••)

: 261 !

^

H

P >

m/z 149 (Xl l ln )

•^ e t c

Cxpertmental

The mass spectra were measured on Jeol JM«S-D 300 at

70 eV. Using direct insertion technique at source tempe

rature of 250°C.

7 8 The benzothiazepine derivatives (I-III, VI^VII and

9 XII, XIII were prepared following the literature procedtare.

The value m/z of the fragment ions from various

compounds are tabulated below. The values in parentheses

are the relative abundance (%) of the peaks with respect

to base peak taken as 100^.

(1) 5a-Cholestan[4a.6-bc1-2'.3'-dihvdro-1'.5'-benzothia

zepine (I) :

493 (13.7), 492 (35.0), 491 (M+*, 100.0), ^^6 (5.0),

458 (3.1), 396 (3.2), 378 (2.0), 368 (2.5), 354 (7.2), 282

: 263 :

(1.5), 244 (4.7), 243 (31.9), 230 (2.7), 229 (4.1), 228

(10.5), 214 (2.2), 200 (3.2), 188 (6.2), 186 (2.7), 175

(4.2), 163 (8.2), 162 (8.1), 150 (9.1), 149 (23.7),

136 (8.2), 135 (5.5), 133 (3.7), 131 (3.3), 125 (3.1),

123 (2.8), 121 (4.1), 119 (4.2), 110 (3.5), 109 (5.2),

107 (6.5), 105 (8.2), 95 (22.2), 93 (9.5), 91 (8.2), 83

(5.2), 81 (11.2), 79 (3.0), 77 (4.7). 71 (7.7), 69 (9.7),

67 (7.7), 57 (14.5), 55 (17.7), 43 (19.7), 41 (14.2).

(2) 5a-Cholestan[4g.6-bc]-2'.3'-dihydro-l'.5*-benzothla-

zepin -3g-vl acetate (II) :

551 (11.9), 550 (40.4), 549 {,tA*'\ 100.0), 534 (1.2),

507 (13.8), 490 (26.6), 489 (56.9), 474 (30.4), 456 (4.5),

436 (2.1), 435 (2.0;, 396 (2.1), 376 (2.0), 352 (11.4;,

280 (2.1), 262 (2.1), 244 (8.5), 242 (11.4), 241 (28.8),

228 (7.6), 227 (2.8), 226 (9.7), 219 (2.6), 200 (7.3;, 199

(7.4), 198 (7.6;, 188 (2.8), 186 (3.5), 163 (9.3), 149

(28.8;, 136 (15.5;, 130 (5.0;, 124 (4.5), 120 (4.2), 108

(4.1), 105 (8.3;, 103 (8.3), 101 (13.1), 95 (l4.i;, 93

118.6), 91 (18.5), 83 (5.7;, 81 (12.l;, 79 (9.i), 77 (6.9),

71 (9.7), 69 (14.1), 67 (9.2), 60 (4.8), 57 (26.2), 55

(28.6), 45 (9.2), 44 (11.4), 43 (49.8).

: 26^ ;

(3) 5 a - C h o l e s t a n l 4 a . t ) - b c 1 - 2 ' . 3 * - c l l h v d r o - l ' . 5 * - b e n z o t h i a -

zepin-Spj-yl p r o p i o n a t e ( I I I ) :

564 ( 1 0 . 0 ) , 563 (M"^; 1 0 0 . O ) , 548 ( 2 . 0 ) , 521 ( 0 . 5 ) , 451

( 1 2 . 0 ) , 490 ( 2 7 . 5 ) , 489 ( 1 7 . 5 ) , 476 ( 3 . 5 ) , 474 ( 6 . 3 ) , 458

( 9 . 5 ) , 456 ( 2 6 . 5 ) , 450 ( l . O ) , 442 ( 1 . 7 ) , 440 ( 2 . 5 ) , 437 ( 2 . 0 ) ,

396 ( 0 . 7 5 ) , 378 ( 2 . 0 ) , 376 ( 0 . 7 5 ) , 352 ( 3 . 5 ) , 334 ( 1 2 . 5 ) ,

330 ( 1 . 7 5 ) , 304 ( l . O ) , 282 ( l . O ) , 280 ( 1 . 0 ) , 266 ( l . O ) , 253

( 1 . 5 ) , 242 ( 2 . 0 ) , 241 ( 2 . 5 ) , 228 ( 6 . 2 ) , 214 ( 3 . 5 ) , 212 ( 1 . 7 ) ,

200 ( 2 . 7 ) , 198 ( 2 . 8 ) , 188 ( 9 . 5 ) , 175 ( 3 . 0 ) , 163 ( 5 . 5 ) , 149

( 9 . 5 ) , 136 ( 1 3 . 3 ) , 12^ ( 7 . 0 ) , 109 ( 5 . 5 ) , 107 ( 5 . 7 ) , 105 ( 6 . 0 ) ,

95 ( 1 1 . 5 ) , 93 ( 1 1 . 8 ) , 91 ( 7 . 5 ) 83 ( 6 . 0 ) , 81 ( 1 1 . 2 ) , 79 ( 7 . 0 ) ,

71 ( 1 4 . 5 ) , 69 ( 1 4 . 6 ) , 67 ( 7 . 5 ) , 57 ( 2 3 . 5 ) , 55 ( 2 3 . 5 ) , 43

( 2 2 . 5 ) .

(^) 5 a - S t i q m a s t a n l 4 a . 6 - b c 1 - 2 ' . 3 * - d i h v d r o - l ' . 5 ' - b e n z o t h i a -

z e p i n - 3 g - v l a c e t a t e (IV) :

577 (M"*"*, 2 2 . 5 ) , 562 ( 1 2 . 5 ) , 561 ( 1 . 2 ) , 549 ( 1 . 5 ) , 535

( 1 . 9 ; , 518 ( 2 . 4 ) , 517 ( 2 . 0 ) , 502 ( 2 . 5 ) , 488 ( 2 . 5 ) , 464 ( 2 . 6 ) ,

436 ( 2 . 9 ) , 400 ( 2 . 5 ) , 382 ( 1 . 9 ) , 358 ( 2 . 6 ) , 340 ( 2 . 7 ) , 299

( 2 . 3 ) , 297 ( 5 . 6 ) , 296 ( 8 . I ) , 295 ( 6 0 . 0 ) , 293 ( 2 3 . 7 ) , 280

( 2 . 5 ) , 2oO ( 6 . 2 ) , 248 ( 1 1 . 2 ) , 242 ( 2 . 0 ) , 241 ( 2 . 2 ) , 228 ( 2 . ^ ) ,

226 {2,1), 214 ( 2 . 6 ) . 212 {3,1), 211 ( 2 7 . 5 ) , 210 ( 3 . 7 ) , 191

( 1 0 . 0 ) , 190 ( 1 0 0 . 0 ) , 134 ( 1 0 . 0 ) , 162 ( l 2 . 2 ) , 149 ( 1 2 . 5 ) , 137

( 2 . 7 ) , 130 ( b l . 2 ) , 13^ ( 1 5 . 0 ) , 125 ( 2 4 . 7 ) , 124 ( 1 8 . 7 ) , 107

: 265 :

( 0 . 2 ) , 105 ( 6 9 . 4 ) , 93 ( 6 . 2 ) , 91 ( 8 . 7 ) , 80 ( 6 . 2 ) , 77 ( 3 0 . 0 ) ,

55 ( 6 . 5 ) , 43 ( 2 . 7 ) .

(5) 5 a - S t i a m a s t a n i 4 a . 6 - b c 1 - 2 ' . 3 ' - d i h v d r o - l ' . 5 ' - b e n z o t h i a -

2eDin-36-v l p r o p i o n a t e (V) :

591 (M"^*, 1 0 0 . 0 ) , 576 ( 1 2 . 5 ) , 549 ( 5 . 2 ) , 535 ( ^ . 5 ) ,

519 ( 8 . 1 ) , 518 ( 8 2 . 5 ) , 517 ( 3 . 5 ) , 516 ( 8 . 1 ) , 502 ( 2 . 5 ) , 436

( 2 . 8 ) , 484 ( 2 . 5 ) , 450 ( 5 . 2 ) , 380 ( 2 . 1 ) , 376 ( 2 . 3 ) , 354 ( 3 . 2 ) ,

297 ( 4 . 2 ) , 296 ( 8 . 2 ) , 295 ( 4 0 . 2 ) , 280 ( 2 . 8 ) , 260 ( 4 . 5 ) , 2^2

( 1 . 8 ) , 241 ( 2 . 2 ) , 228 ( 3 . 1 ) , 226 ( 2 . 5 ) , 214 ( 3 . 1 ) , 212 ( 2 . 8 ) ,

211 ( 6 . 2 ) , 198 ( 3 . 9 ) , 175 ( 2 . 8 ) , 163 ( 5 . 3 ) , 149 ( 1 0 . 2 ) , 136

( 2 2 . 5 ) , 124 ( 5 . 2 ) , 110 ( 5 . 2 ) , 107 ( 5 . 8 ) , 10t> ( 1 0 . 8 ) , 95

( 1 1 . 2 ) , 93 ( 1 0 . 8 ) , 91 ( 7 . 8 ) , 80 ( 5 . 8 ) , 55 ( 1 0 . 2 ) , 43 ( 1 0 . l ) .

(6) 5 a - C h o l e s t a n r 5 . 7 - b c l - 2 ' . 3 ' - d i h v d r o - l * . 5 * - b e n z o t n i a z e c i r . e -

[ y i .

493 ( 9 . 1 ) , 491 (M*"-, 1 0 0 . 0 ) , 476 ( 1 5 . 8 ) , 475 ( ^ 3 . 1 ) ,

406 ( 4 . 6 ) , 378 ( 2 . 1 ) , 318 ( 2 . 0 ) , 296 ( l . O ) , 295 ( 8 . C ) , 283

( 2 . 7 ) , 282 ( 2 . 8 ) , 281 ( 2 . 8 ) , 270 ( 4 . 1 ) , 268 ( 7 . 3 ) , 267 ( 1 0 . 3 ) ,

255 ( 6 . 9 ) , 254 ( 6 . 8 ) , 241 ( 4 . 1 ) , 228 ( 2 . 8 ) , 227 ( 2 . 7 ) , 225

( 2 . 5 ; , 212 ( 1 . 8 ) , 198 ( 1 . 6 ) , 194 ( I . 5 ) , 17c> ( I . 6 ) , 165 ( 1 . 7 ) ,

1C>3 ( 1 . 5 ) , 161 (1.8), 149 ( 1 . 9 ) , 147 ( 1 . 8 ) , 136 ( 5 . 1 ) , 124

( 2 . 1 ) , 121 ( 2 . 2 ) , 108 ( 4 . 8 ) , 105 ( 7 . 1 ) , 95 ( S . 7 ) , 93 ( 3 . 2 ) ,

: 266 :

91 ( 9 . 4 ) , 81 {7.1), 79 ( 7 . 1 ) , 57 ( 1 2 . 6 ) , 55 ( 9 . 1 ) , ^3

( 2 4 . 1 ) , 41 ( 1 1 . 5 ) .

(7) 5 a - C h o l e s t a n r 5 . 7 - b c 1 - 2 ' . 3 ' - d i h v d r o - l ' . 5 ' - b e n z o t h i a -

z e p i n - S e - y l a c e t a t e (VII) :

550 ( 0 . 8 ) , 549 (M""*, 1 .8 ) , 492 ( 0 . 2 5 ) , 491 ( 0 . 3 7 ) , 490

( 0 . 6 9 ) , 489 ( 0 . 7 5 ) , 488 ( 0 . 1 2 ) , 474 ( . 0 7 ) , 473 ( 0 . 1 3 ) , 455

( . 0 6 ) , 436 ( . 4 ) , 427 ( 0 . 2 5 ) , 421 ( 0 . 4 3 ) , 412 ( 0 . 2 3 } , 409

( 0 . 3 6 ) , 408 ( 0 . 6 9 ) , 404 ( 0 . 1 3 ) , 403 (O . IO) , 367 ( 2 . 7 ) , 281

( 1 . 3 ) , 268 ( 1 . 3 ) , 267 ( 5 . 0 ) , 266 ( 3 . 7 ) , 241 ( 7 . 5 ) , 200 ( 8 . 7 ) ,

197 ( 2 2 . 5 ) , 175 ( 1 0 . 0 ) , 165 ( 1 7 . 5 ) , 162 ( 8 . 7 ) , 160 ( 1 3 . 0 ) ,

151 ( 1 2 . 7 ) , 148 ( 2 2 . 5 ) , 140 ( 5 . 0 ) , 136 ( 7 . 5 ) , 133 ( 1 2 . 7 ) ,

124 ( 9 . 2 ) , 119 ( 3 5 . 0 ) , 118 ( 2 2 . 5 ) , 99 ( l 8 . 0 ) , 98 (lOO.O),

96 ( 1 5 . O ; , 93 U 7 . 5 ) , 92 ( 1 5 . 7 ) , 90 ( 1 7 . 5 ) , 84 ( 3 2 . O ; , 80

( 2 0 . 0 ) , 76 ( 1 2 . 5 ) , 70 ( 5 5 . 0 ) , 68 C37.5) , 56 ( 7 7 . 5 ; , 54

( 4 9 . 0 ) , 43 ( 6 2 . 5 ) .

^^^ 5 a - C h o l e s t a n | 5 . 7 - b c 1 - 2 ' . 3 ' - d j h v d r o - l ' . 5 ' - b e n z o t h i a z e o i n -

3g -v l c h l o r i d e (VIIT,) :

527 ( 2 0 . 0 ) , 525 ( 4 6 . 1 ) , 512 ( 0 . 8 9 ) , 510 (2 .2 ) , 492

( 4 . 6 ) , 491 ( 7 . 7 ) . 490 ( 1 8 . 4 ) , 489 ( 1 2 . 3 ) , 474 ( 2 . 3 ) . 405

( 2 . 0 ) , 404 ( 1 . 3 ) . 403 ( 2 . 2 ) , 402 ( 4 . 4 ) , 389 ( 0 . 8 8 ) . 387 ( 2 . 4 ) ,

385 ( 5 . 7 ) . 382 ( 7 . 6 ) , 376 ( 1 . 3 ) , 367 ( 6 . 1 ) , 36c ( lO .O) , 3c5

( C . 9 ) . 350 ( 3 . 1 ) . 339 ( 1 . 5 ) . 324 ( 0 . 7 8 ) , 319 ( 0 . 4 9 ) . 317

: 267 :

( 1 . 2 ) , 301 ( 3 . 3 }, 297 ( 0 . 5 8 ) , 292 ( 0 . 5 9 ) , 290 ( 3 . 3 ) , 238

( 8 . 8 ) , 2 8 1 ( 1 . 2 ) , 274 ( 2 . 5 ) , 268 ( 3 . 9 ) , 260 ( l . S ) , 252 ( 4 . 9 ) ,

246 ( 5 . 5 ) , 241 ( 3 . 7 ) , 227 ( 4 . 5 ) , 213 ( 4 . 6 ) , 210 ( 3 . 4 ) , 201

( 5 . 1 ) , 200 ( 5 . 3 ) , 196 ( 4 . 7 ) , 192 ( 4 . 8 ) , 187 ( 5 . 9 ) , 185

( 1 1 . 3 ) , 175 ( 5 . 9 ) , 174 ( 6 . 5 ) , 172 ( 5 . 9 ) , 161 ( 1 1 . 8 ) , 158

( 9 . 7 ) , 156 ( 1 0 . 5 ) , 148 ( 3 2 . 3 ) , 144 ( 1 4 . 2 ) , 142 ( 1 5 . 1 ) , 136

( 1 0 0 . 0 ) , 124 ( 6 4 . 6 ) , 118 ( 1 5 . 3 ) , 108 ( 1 3 . 5 ) , 106 ( 2 6 . 1 ) , 104

( 2 6 . 2 ) , 94 ( 2 6 . 1 ) , 92 ( 3 3 . 0 ) , 90 ( 2 8 . 4 ) , 8 1 ( 4 6 . 1 ) , 7 1

( 2 9 . 2 ) , 69 ( 2 7 . 6 ) , 57 ( 7 6 . 9 ) , 5-5 ( 5 3 . 8 ) , 4 3 ( 7 3 . 8 ) , 4 1 (64.6)

(9) 5 a - S t i a m a s t a n r 5 . 7 - b c 1 - 2 ' . 3 ' - d l h v d r o - l ' . 5 * - b e n z o t h i a -

zep ine ( lX) :

519 (M"^*, 2.5), 504 (2.2), 503 (2.3), 476 (2.2), 432

(2.2), 378 (1.8), 295 (1.5), 283 (2.4), 282 (2.4), 280 (2.5),

270 (2.6), 268 (2.3), 255 (1.8), 254 (2.2), 243 (2.1), 239

(2.2), 228 (2.7), 224 (2.7), 212 (2.2), 162 (2.1), 148 (8.7),

141 (3.8), 136 (3.7), 127 (7.5), 125 (6.2), 119 (5.6), 113

(9.7), 111 (12.5), 109 (10.0), 106 (7.5), 99 (12.5), 97

(23.7), 95 (16.2), 85 (42.5), 83 (28.7), 81 (20.0), 71(61.2),

69 (38.7), 57 (100.O), 55 (50.0), ^3 (80.2).

^^^^ 5--^-Stiqmastdn[5.7-bc]-9'.3'-dihvdro-l'.5'-bPn7nfni.-

2epin-3lj-vl dcet^^tP (y) ..

577 (M^-, 22.2). 576 (6.2), 535 (12.l), 518 (20.2),

: 268 :

bl7 (50.5), 502 (2.3), 484 (5.5), 455 (2.1), 44C (3.2), 436

(5.1), 421 (2.9), 409 (5.5), 408 (2.8), 404 (5.B), 403 (5.2;,

395 (3.1), 282 (2,8), 281 (4.5), 276 (2.9), 275 (2.7), 267

(3.8), 266 (4.5), 241 (2.6), 200 (5.5), 197 (20.5), 175

(28.9), 163 (5.9), 149 (10.7), 140 (1.5), 136 (8.9), 124

(5.7), 111 (2.8), 109 (5.6), 95 (15.2), 85 (40.5), 81 (10.Ij,

71 (25.7), 69 (35.2), 57 (100.O), 55 (48.2), 43 (57.9).

(11) 5a-Stiqmast-3-enr5.7-bc1-2'.3'-dihvdro-l'.5'-benzothia

zepine (XI) :

517 (M" ', 27.8), 516 (52.7), 502 (33.3), 501 (100.0),

487 (13.9), 474 (2.7), 430 (2.6), 378 (2.1), 293 (11.8), 281

(2.5), 280 (2.5), 278 (2.7), 268 (2.8), 266 (11.l), 252 (9.7),

237 (2.3), 222 (2.2), 221 (2.1), 210 (2.3), 196 (2.1), 163

(2.1), 162 (2.2), 149 (5.5), 136 (8.3), 109 (5.5), 95 (8.3),

85 (5.8), 83 (8.3), 81 (16.6), 71 (13.2), 69 (13.9), 57

(33.3), 55 (20.8), 43 (38.9).

(12) N.S-Phenvlene-3g-thio-3S-amlnocholest-4-ene (XII) :

491 (M •, 87.5), 490 (8.0), 489 (3.7), 477 (5.5), 476

(20.0), 463 (3.2), 459 (2.5), 458 (2.2), 378 (2.5), 243(2.5).

242 (6.2), 240 (2.7), 231 (3.2), 230 (5.5), 229 (5.7), 228

(5.6;, 227 (1.2), 226 (2.7), 216 (3.0), 214 (7.5), 203 (3.7),

: 269 :

164 ( 6 . 7 ) , 163 ( 1 5 . O ; , 162 (100 .O} , 150 ( 7 . 0 ) , 149 ( 3 0 . 0 ) ,

137 ( 2 . 2 ) , 136 ( 1 2 . 0 ) , 125 ( 6 . 7 ) , 124 ( 4 . 7 ) , 110 ( 7 . 5 ) , 109

( 6 . 2 ) , 107 ( 8 . 2 ) , 105 ( 1 2 . 0 ) , 95 ( 1 2 . 5 ) , 93 ( 8 . 2 ) , 91 ( 1 1 . 0 ) ,

81 ( 1 3 . 2 ) , 79 ( 8 . 0 ) , 77 ( 7 . 5 ) , 71 ( 1 0 . 2 ) , 69 ( 1 3 . 7 ) , 6 7 ( 9 . 5 ) ,

57 ( 2 3 . 7 ) , 55 ( 2 1 . 2 ) , 44 ( 1 7 . 5 ) , 43 ( 2 7 . 7 ) .

(13) 5 a - C h o l e s t a n l 2 a . 4 a - b c ] - 2 * . 3 ' . 4 * . 5 * - t e t r a h y d r o - l * , 5 ' -

b e n z o t h i a z e p i n - 6 - o n e ( X I I I ) :

508 ( 3 6 . 0 ) , 507 (M"^*, 1 0 0 . 0 ) , 506 ( 3 . l ) , 492 ( 3 . 7 ) ,

489 ( 1 . 4 ) , 479 ( 8 . 9 ) , 464 ( 0 . 9 ) , 431 ( 5 . 6 ) , 40O ( 8 . 4 ) , 394

( 1 . 8 ) , 382 ( 1 . 4 ) , 381 ( 1 . 5 ) , 380 ( 1 . 4 ) , 370 ( l . l ) , 2 8 7 ( 2 . 3 ) ,

260 ( 0 . 6 ; , 259 ( 1 . 2 ) , 247 ( 1 . 4 ) , 246 ( 2 . 1 ) , 245 ( 4 . 2 ) , 231

( 1 . 6 ) , 230 ( 1 . 1 ) , 218 ( 2 . 8 ) , 2 i 7 ( 2 . 3 ; , 216 ( 4 . 7 ) , 2 0 7 ( 2 . 8 ) ,

206 ( 2 . 8 ) , 205 ( 1 1 . 2 ) , 204 ( 1 4 . 9 ) , 190 ( 3 . 7 ) , 189 ( 4 . 6 ) ,

176 ( 2 . 8 ) , 175 ( 4 . 2 ) , 164 ( 6 . 5 ) , 163 ( 1 7 . 7 ) , 162 ( 7 9 . 6 ) , 150

( 7 . 4 ) , 149 ( 7 3 . 8 ) , 136 ( 5 . 6 ) , 124 ( 6 . 6 ) , 121 ( 5 . 1 ) , 109

( 6 . 1 ) , 107 ( 6 . 1 ) , 105 ( 5 . 1 ) , 95 ( 8 . 4 ) , 93 ( 7 . 9 ) , 81 ( 8 . 9 ) ,

69 ( 8 . 9 ) , 57 ( 1 4 . 0 ) , 55 ( l 6 . 4 ) , 44 ( 3 9 . 3 ) , 43 ( 2 5 . 5 ) , 32

( 5 8 . 9 ) .

JleCerentejBf

1. H. Budzikiewicz, C. Djerassi and D.H. William,

Structure elucidation of natural products by mass

spectrometry, Part II» Holden-Day, San Francisco

(1964).

2. R. Bangelmans, R.H. Shapiro, L.J. Durham, D.H.

Williams, H. Budzikiewicz and C. Djerassi,

J. Am. Chem. Soc, ^ , 2832 (1964).

3. H. Budzikiewicz and C. Djerassi, J. Am. Chem. Soc,

34, 1430 (1962).

4. C D . MacDonald, J,S, Shannon and G. Sugowdz,

Tetrahedron Letters, 807 (1963).

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iHEMICAL INVEBTieATION 2YOLIC SYSTENB WITH Si …RESUME ,.._..._ u C_ ) ! THESES SUBMITTED FOR THE...

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